|Posted on December 13, 2020 at 6:25 PM||comments (0)|
There is no way that you can get big and strong on a vegetarian diet! I used to hear this all the time from my meat-eating friends. I say, used to as I never hear it anymore from people that know me or from people that have seen my photos on my website. Yes my friends, you can in fact get bigger and stronger on a vegetarian diet. You can even do it on a vegan diet (no animal products whatsoever).
How To Get Started
When I was fifteen I read an interview with Harley Flannagan (lead singer of the legendary NYC hardcore band, the Cro-mags) in which he stated that he became a vegetarian to lead a more peaceful life and that one cannot talk about peace when they have a steak on their plate, as an animal died in agonizing pain to end up there. That really struck a cord with me and got me thinking about the thousands of animals that suffer daily on factory farms. Next, I visited Kenya with my parents and experienced a feeling of oneness with the animals over there.
I realized that I did not want to contribute to the unnecessary suffering of other beings and I knew that I needed to make some changes. Finally, I saw a movie called "The Fly II" in which a golden retriever is mutilated in an experiment gone bad. That got me thinking about how animals are abused in labs and further solidified the new direction that I was taking. In addition, to giving up meat, I decided that I would make sure to purchase products such as: toothpaste, shampoo, soap etc that were not tested on animals.
I gave up meat gradually. I stated off by giving up all meat except fish. Then I gave up fish, but continued to eat eggs and dairy. Once I realized that most eggs and dairy products came from animals that lived miserable lives on factory farms, I gave up all animal products. That was ten years ago and I have never looked back. While I am an ethical vegan, there is no doubt in mind that a vegan diet is healthy and that I can get everything that my body need for my intense lifestyle. Regardless, like any other diet, planning is required.
The number one thing that people always ask me is where do I get my protein. Many vegans that I have met make the mistake of thinking that you do not need much protein at all. I even had one guy tell me that only 5% of one's diet should come from protein. Of course this guy looked like Don Knots and would be blown off like kite if a strong wind came by. I had another guy tell me that I can get protein from a cucumber and that I should not even worry about it.
Of course, this guy was not in shape either and was in no position to give me nutrition advice. We have to be much more sensible than that. Especially, if we expect anyone to give up meat and adopt a vegetarian diet. Telling people that they can get all of the protein that they need from eating spinach and leafy green vegetables is impractical. Just because it works for the gorillas does not mean that it will work for us. Not getting enough protein and thinking that only 5% of your diet needs to be comprised of protein are sure fire ways to be spindly and weak for the rest of your life. Now I am not saying that you need two grams of protein per pound of bodyweight like the bodybuilding magazines state.
That is way too much protein and a case of overkill. For athletes, 0.7 to 1 gram of protein per pound of lean muscle is optimal for increasing strength and size. For example, if you weigh 180lb and have ten percent bodyfat, then you should shoot for 150-160 grams of protein to build more muscle. If you want to maintain your size, then 100-120 will probably be sufficient.
Next, vegans like anyone else need to load up on healthy sources of fat. Without enough fat in your diet, your skin will dry up, your energy will plummet, and you will look like death. Getting 20-30% of your calories from fat is a good way to go. Load up on healthy fats such as: flaxseed oil, olive oil, almonds, walnuts, almond butter, and avocadoes. Also, vegan diets are free of all saturated fats, which is great for the most part. However, some saturated fat is required for optimal health, so get some coconut oil or coconut milk in you diet as well.
Finally, make sure that you eat a variety of food to get a full array of muscle building amino acids. Some examples of good combinations include: black beans and quinoa, lentils and brown rice, almond butter sandwich, rice protein/soy milk shake, green peas and almonds. Have some veggie burgers and other fake meat products from time to time, but make sure that the majority of your diet comes from fresh organic food.
|Posted on December 13, 2020 at 6:20 PM||comments (0)|
The connection between IGF-1—also known as the insulin-like growth factor 1—and the human growth hormone (HGH) for healthy aging is complex.
If excessive levels –low or high– of IGF-1 are present in the body, they could lead to some health problems. Additionally, HGH is generally considered to employ anti-insulin actions, whereas IGF-1 has insulin-like properties. Maintaining relatively low levels of IGF-1 and synergy between HGH and IGF-1 throughout most of one’s adult life is an important factor by which adults can live a healthy lifestyle and experience an optimal aging process.
HUMAN GROWTH HORMONE (HGH) AND INSULIN-LIKE GROWTH FACTOR-1 (IGF-1) PLAY ESSENTIAL ROLES IN HEALTH
HGH and IGF-1 play essential roles in childhood growth and continue to serve important metabolic functions in adults. One of the conditions that may affect healthy aging includes low levels of growth hormone presenting in adults. This condition is mainly characterized by increased visceral adiposity, abnormal lipid profiles, decreased quality of life, and other important risk factors.1 Interestingly, HGH deficiency in adults predisposes insulin resistance.2 High doses of HGH treatment have major effects on lipolysis, which plays a crucial role in promoting its anti-insulin effects. On the other hand, IGF-1 acts as an insulin sensitizer that does not exert any direct effect on lipolysis or lipogenesis.3
Unlock the potential of human growth hormone (HGH). Find out how in our white paper.*
THE ROLE OF HGH AND IGF-1 IN METABOLISM AND AGING
Research shows that one’s metabolism slows down with age. A few reasons for this include less physical activity (exercise), muscle loss (sarcopenia), and the normal aging of the organs. Additionally, loss in lean body mass and muscle tissue can be detrimental when it comes to ill adults. Yet HGH has major effects on metabolism. It has been shown that HGH’s potential benefits when it comes to protein metabolism.4 Some of the functions of HGH are facilitated through IGF-1. Administration of HGH induces a rise in circulating IGF-1 that stimulates glucose and amino acid uptake in muscle, which improves muscle protein synthesis.4 In catabolic circumstances, the levels of IGF-1 decrease while its binding proteins increase, leading to a lower local IGF-1 activity and contributing to the decreased insulin sensitivity seen in catabolism.5
The metabolic effects of HGH are, in part, mediated through IGF-1 produced in the liver and in the peripheral tissues influenced by HGH.5 In skeletal muscle, a reduced gene-expression of the HGH-receptor can occur. This reduces the local IGF-1 synthesis, an effect that may be offset by HGH supplementation.* Change in the GH/IGF-1 can possibly counteract through amino acid supplementation.*6,7,8,9 Specific amino acids—such as arginine, lysine, and ornithine—can stimulate HGH release when infused intravenously or administered orally. It has also been demonstrated that glycine is also one of the stimulatory agents inducing the pituitary gland to secrete HGH.8 These are all important amino acids utilized in the growth of HGH.
As specified above, a combination of HGH and IGF-1 has beneficial potential because the decreased insulin sensitivity induced by HGH can be outbalanced by the addition of IGF-1. In general, HGH increases the binding protein for IGF, and concomitant administration may, therefore, increase the bioavailability of IGF-1 and its effects on the tissues.2,6,7,8,9
HAVING ADEQUATE LEVELS OF IGF-1 IS EXTREMELY IMPORTANT FOR THE ELDERLY
Having low levels of IGF-1 in the elderly is linked to developmental changes. Adequate levels of IGF-1 are needed for the maintenance of bone mass, muscle mass, and brain function at later ages.9
In order to extend a patient’s lifespan, the goal should be to maintain a relatively low IGF-1 throughout most of their adult life. Then, once they reach the age of eighty, they should consume enough protein along with the amino acids arginine, lysine, ornithine, and glycine necessary to prevent their IGF-1 level from becoming excessively low.
It is also important to pay attention to their diet to ensure that their IGF-1 levels are favorable throughout their lives.
HOW IGF-1 WORKS IN THE HUMAN BODY
As previously mentioned above, IGF-1 is a hormone with a similar structure to insulin as well as a cell growth-promoter important for brain development and muscle and bone growth during childhood. HGH from the pituitary gland stimulates IGF-1 production in the liver and IGF-1 levels peak during the teenage years and twenties, but those levels start to decline as one ages.10,11
The intake of protein and amino acids regulates IGF-1 circulating in the body. Animal protein has high levels of all the essential amino acids, thus it can trigger excessive body production of IGF-1, whereas plant protein does not.12,13 Still, if animal protein is not an option, there are other ways to consume these amino acids. Finally, high-glycemic, refined carbohydrates can also raise IGF-1.14
WHAT ARE THE OPTIMAL IGF-1 LEVELS?
One study, conducted in Europe, found the following averages for IGF-1 levels in healthy patients of different age ranges:15
Average Serum IGF-1 (ng/ml)
The study reported an average serum IGF-1 level of 200-210 ng/ml, suggesting that this is the typical level for adults on a Western diet.16 The amount of animal products consumed by most Americans drives their IGF-1 into danger quantities (above 200), increasing their risk of other conditions.
Therefore, it is important to keep in mind that low IGF-1 levels also increase the risk of health complications, these levels being generally about 70-80 ng/ml or lower.12,13,14,17 Studies in elderly men (average age 75) have found an increased risk of cardiovascular problems in high IGF-1 groups (approximately 190 ng/ml).12,15,18,19,20,21
By taking all this information into account, most adults must keep IGF-1 below 175 ng/ml or even 150 ng/ml if possible. At the same time, serum IGF-1 levels below 80 ng/ml can be detrimental, especially after the age of 75.22,23
In essence, restricting the consumption of animal protein to maintain a relatively—but not excessively—low IGF-1 is an important objective for optimal aging. Since protein digestion and absorption can decline during the elderly years, adopting a more nutritional diet and lifestyle may be helpful for protein tolerability while aging, along with preventing the excessive lowering of IGF-1 commonly seen with other plant-based diets. To achieve greater micronutrient completeness, patients can add important amino acids like arginine, lysine, ornithine, and glycine, along with other sources of protein to their diets.
Indexed for Davinci Labs by Dragonfly Kingdom Library
|Posted on December 13, 2020 at 6:15 PM||comments (0)|
Background and objectives
A plant-based diet is an effective strategy in the treatment of obesity. In this 16-week randomized clinical trial, we tested the effect of a plant-based diet on body composition and insulin resistance. As a part of this trial, we investigated the role of plant protein on these outcomes.
Subjects and methods
Overweight participants (n = 75) were randomized to follow a plant-based (n = 38) or a control diet (n = 37). Dual X-ray Absorptiometry assessed body composition, Homeostasis Model Assessment (HOMA-IR) assessed insulin resistance, and a linear regression model was used to test the relationship between protein intake, body composition, and insulin resistance.
The plant-based vegan diet proved to be superior to the control diet in improving body weight, fat mass, and insulin resistance markers. Only the vegan group showed significant reductions in body weight (treatment effect −6.5 [95% CI −8.9 to −4.1] kg; Gxt, p < 0.001), fat mass (treatment effect −4.3 [95% CI −5.4 to −3.2] kg; Gxt, p < 0.001), and HOMA-IR (treatment effect −1.0 [95% CI −1.2 to −0.8]; Gxt, p = 0.004). The decrease in fat mass was associated with an increased intake of plant protein and decreased intake of animal protein (r = -0.30, p = 0.011; and r = +0.39, p = 0.001, respectively). In particular, decreased % leucine intake was associated with a decrease in fat mass (r = +0.40; p < 0.001), in both unadjusted and adjusted models for changes in BMI and energy intake. In addition, decreased % histidine intake was associated with a decrease in insulin resistance (r = +0.38; p = 0.003), also independent of changes in BMI and energy intake.
These findings provide evidence that plant protein, as a part of a plant-based diet, and the resulting limitation of leucine and histidine intake are associated with improvements in body composition and reductions in both body weight and insulin resistance.
Suboptimal nutrition is a major cause of obesity, chronic disease, and premature death across the nation and worldwide1,2. Certain dietary habits, such as high intakes of sodium and processed meat products and low intakes of fruits and vegetables, are associated with 45.5% of cardio-metabolic deaths in the United States3. Fortunately, research has shown a plant-based vegan diet to be beneficial in improving nutrient intake4, decreasing all-cause mortality, and decreasing risk of obesity, type 2 diabetes, and coronary heart disease5.
A plant-based vegan diet excludes all animal products and is centered around grains, legumes, vegetables, and fruits. While adequate in macro and micronutrients6, people sometimes question the ability to reach protein requirements on a plant-based vegan diet. A sufficient protein intake is necessary to supply nitrogen and amino acids to our cells to ensure the growth and maintenance of the protein pool in our bodies7. However, a diet based entirely on plants provides all essential amino acids and an adequate quantity of overall protein, even without the use of special food combinations6. Further, the consumption of exclusively plant proteins has been associated with reduction of the concentrations of blood lipids8,9,10,11, obesity12, and cardiovascular disease13,14,15.
The specific composition of dietary protein has been shown to influence the balance of glucagon and insulin activity14, which may play a role in body composition and insulin resistance12. A high intake of branched chain amino acids (leucine, isoleucine, and valine) can increase insulin resistance16. In addition, dietary restriction of sulfur containing amino acids (methionine and cysteine), is associated with a reduction in body weight, adiposity and metabolic changes in both adipose and liver tissues, which enhance insulin sensitivity and energy expenditure17. Plant protein low in sulfur also reduces blood lipids, homocysteine, and blood pressure18,19. Furthermore, low protein diets are also associated with increased life span, especially if the consumed protein is plant derived20.
In this secondary analysis of data from a 16-week randomized clinical trial21, we explore the effects of plant protein, as part of a plant-based diet, on weight control, body composition, and insulin resistance in overweight individuals.
This study demonstrated that the quality and quantity of dietary protein from a plant-based vegan diet are associated with improvements in body composition, body weight, and insulin resistance in overweight individuals. A decreased intake of animal protein and an increased intake of plant protein were associated with a decrease in fat mass, by 1.45 and 0.88 kg respectively. Exchanging plant protein for animal protein explains more than half of the reduction in fat mass in the vegan group (2.33 out of 4.3 kg). A large portion of fat mass reduction may be explained by the amino acid composition of plant protein, specifically by decreased leucine intake, which was associated with a decrease in fat mass by 0.82 kg, independent of changes in BMI and energy intake. Additionally, decreased histidine intake was associated with a decrease in insulin resistance, also independent of changes in BMI and energy intake. Finally, decreased intakes of threonine, leucine, lysine, methionine, and tyrosine were each associated with a decrease in insulin resistance. However, these associations were mainly driven by weight loss.
Plant vs. animal protein in weight regulation, body composition, and insulin resistance
Multiple randomized controlled studies have established the effectiveness of plant-based diets for weight loss25,26. Plant-based diets have also been shown to decrease the risk of developing diabetes in additional prospective studies27. The specific role of plant protein in weight regulation and metabolic health is of particular interest. In a study focusing specifically on the association between protein sources and body weight regulation using data from the European Prospective Investigation into Cancer and Nutrition study, increases in body weight were positively correlated with an increased intake of animal protein, especially in women28. Similarly, in a 2011 observational study, increases in animal protein consumption were found to be positively correlated with increases in BMI, while increases in plant protein intake were negatively associated with changes in BMI29.
Dietary protein triggers release of both insulin and glucagon12. Specifically, a higher intake of essential amino acids can stimulate secretion of insulin and up-regulate insulin like growth factor 1 (IGF-1)12. Essential amino acids are found in greater abundance in animal protein, compared to plant protein. In contrast, a higher intake of non-essential amino acids is associated with down-regulation of insulin secretion and increased glucagon secretion, resulting in stimulation of gluconeogenesis, hepatic lipid oxidation, lipolysis and reduction in both IGF-1 and cholesterol synthesis. Hepatic lipid oxidation promotes appetite control and lowers the respiratory quotient, which may play a role in body weight reduction, and may further be supported by the thermogenic effect of glucagon. Human adipocyte express IGF-1 receptors, thus down-regulation of IGF-1 activity can also promote leanness12. Non-essential amino acids in plant protein promote higher net glucagon activity than an omnivorous diet, promoting weight loss and reduction of LDL-cholesterol12.
The role of specific amino acids in insulin resistance and weight regulation
A 2018 prospective study that included more than 1,200 adults, who were followed-up for a mean of 2.3 years, showed that higher intake of branched chain amino acids (BCAA), especially leucine, can increase insulin resistance. Participants in the highest tertile for leucine intake had a 75% higher risk of developing insulin resistance compared with people in the lowest tertile (OR 1.75; 95% CI 1.09–2.82)16.
Increased serum concentrations of BCAA have been associated with increased risk of type 2 diabetes and underlying metabolic abnormalities30,31. High serum BCAA levels activate the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, leading to inhibition of glucose transport in muscle and fat tissues16. Animal protein from meat and dairy products contains a high percent of leucine. Therefore, these foods may stimulate the mTORC1 pathway, thus contributing to insulin resistance, and obesity32.
Randomized controlled trials have shown that reduced dietary intake of BCAA promote weight loss, reduce adiposity, and improve glycemic control and metabolic health33,34. In our study, the vegan group consumed less than 75% of the control group’s daily grams per day of BCAA. Our data also show that reduced dietary intake of leucine, in particular, was associated with decreased fat mass and reduced insulin resistance.
Additionally, our results suggest that a decreased intake of histidine, leucine, threonine, lysine, methionine, and tyrosine were all associated with a decrease in HOMA, with histidine being the only one having a significant association independent on changes in BMI and energy intake. The vegan group reduced both its absolute and relative intake of all six of these amino acids. The significant decrease in the consumption of sulfur-containing amino acids, i.e. cysteine and methionine, in the vegan group, is of particular interest. Several studies have shown that diets restricting sulfur-containing amino acids have shown beneficial effects in the prevention of chronic diseases, including type 2 diabetes, cancer, and cardiovascular disease14,17. Dietary restriction of methionine and cysteine without caloric restriction has been associated with reductions in body weight, adiposity, blood levels of insulin, IGF-1, and glucose17, as well as reductions in cardiovascular risk factors including blood lipids, homocysteine, and blood pressure18,19. Our results suggest that reduced intake of methionine through a plant-based diet may correlate with a decrease in both body weight and insulin resistance.
Meeting and exceeding the recommended daily intake on a plant-based diet
Higher animal protein consumption has been associated with increased risk of metabolic disease and mortality. A 2015 study using data from NHANES II reported the link between protein intake and mortality in men and women. Subjects in the high-protein group (consuming 20% or more of daily calories as protein) had a 73-fold increase in risk of diabetes mortality and a 74% increase in relative risk of all-cause mortality20. Our data suggest that both the decreased intake of animal protein and the amino acid composition of the plant-based diet are associated with decreased body fat and reduced insulin resistance.
The United States Department of Agriculture recommends a minimum of 46 g of protein per day for women and 56 g per day for men35. In the current study, all participants in the vegan group exceeded the recommended daily intake of protein and of each individual amino acid. While animal protein is higher in essential amino acids, containing significant amounts of leucine, histidine, threonine, methionine and lysine, consumption of plant protein, which is higher in non-essential amino acids, offers clear metabolic benefits. People following a plant based diet still consume more than 100% of the recommended dietary intake of essential amino acids. The main plant sources of these amino acids are legumes, grains, and vegetables. For example, 2 servings of oatmeal made from 100 g of oats contain 102% of recommended daily intake of tyrosine36.
|Posted on December 13, 2020 at 6:15 PM||comments (0)|
As many of you know by now, I strongly recommend a whole food, plant-based diet to combat cancer. The question I continually get is, “where do you get your protein?”
If you review the protein recommendations of the US government you can use the following equation to get your protein requirement:
Pounds X 4 divided by 10.
My weight is 155 pounds. Therefore 155 X 4 = 620.
620 divided by 10 = 62 grams.
If you use the metric system use kilograms X 0.8.
I eat a strict whole food, plant-based diet (no animal products) and I have checked my protein intake on consecutive days for a whole week and I normally get over 100 grams per day, which in my view is more than my goal.
The average Westerner who eats a lot of meat and dairy products is easily getting 2-3 times the recommended about of protein and this can be harmful to one’s health and especially someone who is combatting cancer. For now, let’s look at some of the negatives of high meat, dairy and protein consumption.
One of the concerning aspects of high animal protein consumption is that it stimulates the liver to produce a growth promoting hormone called “Insulin-like Growth Factor-1 (IGF-1)” which at higher levels in adults has been shown to be a major instigator of cancer initiation and growth [1,2]. This does not happen when the liver is exposed to incomplete plant proteins. Apparently, because animal protein is a complete protein, it sends a signal to the liver that growth is about to occur, so IGF-1 is manufactured. In studies, meat eaters consistently are shown to have much higher IGF-1 levels compared to vegans.
When we are young our body needs IGF-1 for growth to allow us to become a full grown adult. Our levels normally peak in our late teens, then gradually decline every year as we age. This gradual decline is built into our bodies to help us stay alive, because as we age we also accumulate thousands of DNA mutations. We do not want a stimulus for high cellular growth and replication in the setting of high levels of DNA mutations. This is a device that Nature has built in to protect us from cancer initiation, growth and metastasis.
It is also important to note that since IGF-1 can promote muscle growth, growth hormone has been promoted and prescribed by anti-aging physicians as an anti-aging hormone. However, studies are finding that restoring growth hormone levels to youthful levels in adulthood is not beneficial; in fact it has been found to increase death rates in formerly healthy adults.
High mTOR Activation
Another promoter of cancer growth in the body is the mTOR gene . This gene is a potent promoter of cellular growth and replication (similar to IGF-1) and as we just learned we do not want a growth stimulator in the setting of increasing mutations. Through scientific study we have learned that the amino acid “leucine” is the most powerful stimulator of mTOR. And guess where leucine is found in high levels? You guessed it. There are high levels in all animal products and very low levels in plant foods. Therefore lowering animal products while increasing plant intake, lowers leucine levels, which lowers mTOR activity. This is an effective way to decrease cancer initiation and growth.
High animal protein intake also puts inordinate stress on the kidneys and after chronic exposure creates damage to the kidney micro-tubules. Animal protein, but not vegetable protein, causes what is called “kidney hyper-filtration” . This is an inflammatory response in the kidney caused by high levels of sulfur-containing amino acids that are present in animal proteins. When anti-inflammatory drugs are given at the time of animal protein ingestion the hyper-filtration does not occur. This hyper-filtration also does not occur with the ingestion of vegetable protein. Furthermore, high animal protein consumption is extremely acidic which puts additional stress on the kidney while also, in the cancer patient, creating a favorable pH for enzymes like “collagenase” to assist the cancer to progress and metastasize .
High Pesticide and Endotoxin Levels
Because all animals are high on the food chain, various retrospective studies always reveal much higher levels of pesticides and heavy metals in the blood and tissue of meat eaters versus vegans. To help you understand this concept, if a grasshopper ate a bunch of pesticide-laden grass, it would absorb those pesticides that would then be dissolved into its fat tissue....something we call “bioaccumulation”. A bird then eats many grasshoppers. The bird’s pesticide levels will now be greater than the grasshopper’s levels. If a human eats a lot of the birds, a chicken for example, the human’s levels will be higher than the chicken’s. A similar situation occurs in the oceans. If you analyze mercury and PCB levels in small fish versus large fish, like tuna, the larger fish will consistently have much higher mercury and PCB levels than the smaller fish.
One of many studies analyzing this bioaccumulation was published in the British Journal of Nutrition and it found that PCB levels were much higher in meat eaters compared to vegans . Similar studies routinely demonstrate this same result... pesticides and heavy metals blood and tissue levels are consistently much higher in meat and dairy consumers.
Animal products also carry viruses like bovine leukemia virus (implicated in 37% of all US breast cancers and also non-Hodgkins lymphoma) and bacterial endotoxins that cannot be destroyed by heat and create much inflammation and negative health issues in the body.
Animal products contain ZERO fiber! 97% of the US population does not get the 30 grams/day of fiber recommended by the US government. This is due to the fact that the average American consumes 50% processed foods, 40% animal products and 10% unrefined plant foods. In a 2010 study, it was found that the average American eats, on average, 1.8 servings of fruits and vegetables per day. And that was allowing French fries and ketchup to be counted as a vegetable!
Fiber has been shown to be critical to creating the right balance in the 30 trillion bacteria that grow in our intestinal tract. These bacteria are many times referred to as “the microbiome”. There are 2 primary groups of bacteria in our GI tract....good Prevotella probiotic bacteria and bad Bacteroides bacteria. There are approximately 500 subspecies in each group. When one is eating at least 30 grams of fiber per day, the good Prevotella probiotic bacteria feed on the fiber, proliferate, and produce short-chain fatty acids which are extremely anti-inflammatory and are said by many experts in the field of immunology to control up to 80% of our immune function.
These short-chain fatty acids also stimulate the FFAR2 receptors on our cells which have a profound control over our metabolism. In rat studies when you feed high concentrations of fiber rich plant food (with no meat) to the rats, they become slim. Conversely, when you feed them high concentrations of animal products (with no plants) they become obese. When we eat primarily processed and animal foods the bad Bacteroides bacteria proliferate and the good probiotic Prevotella bacteria decrease, causing many chronic diseases and weight gain. Conversely, when we eat lots of fruits, vegetables, whole grains, beans, nuts and seeds, the good probiotic Prevotella increase in numbers and the harmful Bacteroides decrease. This latter scenario puts us in a much better position to enjoy maximal health.
This is the most important factor that causes me to recommend limiting animal product consumption. Plants have over 25,000 phytonutrients that have profound antioxidant, anti-inflammatory and anti-tumor effects in the body. Animal products have none of these phytonutrients.
Because of this fact, plants foods have been found to have 63X the antioxidant power compared to animal products. ORAC (oxygen radical absorbance capacity) units are the units that we use to measure the ability of foods to neutralize health-damaging free radicals. For those of you who are unfamiliar with free radicals, they are molecules with unpaired electrons that are created daily by our cells in the trillions. These free radicals will seek out another electron to create a neutral electrical charge, however in the process of finding an electron mate, they create thousands of DNA mutations in our lifetime which are at the root of all cancers. Innate intracellular antioxidants (glutathione peroxidase, superoxide dismutase and catalase), along with the antioxidants that we eat, can neutralize most of these free radicals, but the Standard American Diet can easily create free-radical overload. Therefore we must complement our innate intracellular antioxidants with a healthy dose of antioxidants from our food intake.
To demonstrate the difference between plant foods and animal products let’s compare one food (a sweet potato) to a whole day of eating a Standard American Diet.
One sweet potato with a teaspoon of cinnamon and a pinch of clove is 246 ORAC units. On the other hand, a morning Egg McMuffin, an afternoon Big Mac and an evening steak with parsley would total 44 ORAC units for the entire day! Every morning I drink a morning smoothie with various fruits, freeze dried powders, ground flax seeds and kale. That smoothie has 2,000+ ORAC units. An analysis of 5 Standard American Diet breakfasts revealed anywhere from 8-25 ORAC units for each of these typical American breakfasts. The dissimilarity is mind blowing!
In an interview, Dr. Nikhil Munshi, a famous myeloma genomic scientist, stated that at the time of myeloma diagnosis, a myeloma patient’s cancer cell has approximately 5,000+ mutations at diagnosis and at relapse about 12,000+. Therefore minimizing the number of mutations is critical for any cancer patient to help them to stay in remission. It is also extremely important for those trying to avoid cancer in the first place.
We all know that eating high cholesterol foods leads to high cholesterol blood levels which then leads to cardiovascular disease. This fact has been validated in thousands of studies over the past 50 years. And what is the only kind of food that contains cholesterol? You guessed it....animal products.
Cholesterol, however, does not only affect the cardiovascular system, it also has a significant effect on cancer. Many of us have heard that cancer needs an enormous amount of sugar to maintain itself due to the fact that it uses a very crude fermentation method of energy production called “Warburg’s aerobic glycolysis”. This method of energy production takes one molecule of glucose and creates only 2 ATP energy molecules. Our normal cells, on the other hand, create 36 ATP molecules from one glucose molecule. Therefore, cancer needs a prodigious amount of glucose just to maintain itself.
There are, however, other nutritional pathways that cancer can use. In Jane McLelland’s excellent and heavily-researched book How to Starve Cancer she demonstrates, through careful analysis of the scientific literature, how cancer can also use a cholesterol pathway and a glutamine (amino acid) pathway for energy production. In fact, some cancers like prostate, colon and breast cancer may even prefer the cholesterol pathway. In fact, there are studies that demonstrate that individuals who take statin drugs have much lower rates of the aforementioned cancers. To understand this concept better, I would highly recommend viewing the 5 minute video on nutritionfacts.org entitled Cholesterol Feeds Breast Cancer Cells.
Therefore cancer patients need to keep their total cholesterol level below 150 and their LDL cholesterol below 80. The absolute best way to do that is with a whole food, plant-based diet. If additional help is needed I recommend Chinese Red Yeast. The product that I use is Beni Koji RYR (Douglas Labs) which can be purchased on Amazon. I take 2 in the morning and 2 in the evening. I also take Ubiquinol-QH (Douglas Labs) with it to keep the CoEnzyme Q10 levels from getting to low. This can also be purchased on Amazon. I take 2 in the morning and 2 in the evening.
Heterocyclic amines are potentially carcinogenic chemical compounds formed in cooked muscle tissue. Examples of heterocyclic amines include harmane, which may cause essential tremor and PhIP, considered an estrogenic carcinogen that may increase breast cancer risk. Poultry meat appears to have the highest concentration of heterocyclic amines, but muscles are not the only source of these toxins. These carcinogens may be present in eggs, cheese, creatine supplements and cigarette smoke.
There are some measures that those who eat meat can do to reduce the risk of developing cancer. Boiling appears to be the safest cooking method in terms of carcinogen levels. Other foods may also decrease the risk. For example, cruciferous vegetables have been shown to reduce the absorption of heterocyclic amines for as long as 2 weeks after consumption. White and green tea may also be protective. If you don’t eat meat for just one day your levels of PhIP and MelQx will drop to zero in just twenty-four hours. Veggie meat is a safe bet since it contains no muscle tissue.
You can see that meat consumption has many negative health effects. A good culmination of what I have just shared with you was extremely well presented in a study by the National Health Institute and The World Health Organization where they looked at the diets of different countries throughout the world. They studied the percentage of unrefined plant consumption in each country and how it correlated with the percentage of people dying from cancer and cardiovascular disease.
In the United States, for example, the average person eats 10% of their diet in unrefined plant foods and we find that 90% of Americans die of either cancer or heart disease. Conversely, in Laos the average person eats over 90% of their diet in unrefined plant foods and only 5% of people in that country die of cancer and heart disease. In Greece, the average person eats a diet that is 35% unrefined plants and 35% of people die of cancer or heart disease. In this study it is absolutely fascinating how the percentage of plant foods directly correlates with the percentage of people dying from cancer and heart disease. The more plants...the less cancer and heart disease.
1. Werner H, Bruchim I. The insulin-like growth factor-1 receptor as an oncogene. Arch Physiol Biochem 2009; 115:58-71.
2. Chitnis MM, Yuen JS, Protheroe AS et al. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res 2008; 14:6364-70.
3. Wang Z et al. mTOR co-targeting strategies for head and neck cancer therapy. Cancer Metastasis Rev 2012; Sept;36(3):491-502.
4. Helal I et al. Glomerular hyperfiltration:definitions, mechanisms and clinical implications. Nat Rev Nephrol 2012; Feb;21;8(5):293-300.
5. Huang S et al. Acidic extracellular pH promotes prostate cancer bone metastasis by enhancing PC-3 stem cell characteristics, cell invasiveness and VEGF-induced vasculogenesisof BM-EPCs. Oncol Rep 2016; Oct;36(4):2025-32.
6. Arguin H et al. Impact of adopting a vegan diet or an olestra supplementation on plasma organochlorine concentrations:results from two pilot studies. Br J Nutr 2010; May;103(10):1433-41.
|Posted on December 11, 2020 at 1:55 PM||comments (0)|
The “chemical obesogen” hypothesis conjectures that synthetic, environmental contaminants are contributing to the global epidemic of obesity. In fact, intentional food additives (e.g., artificial sweeteners and colors, emulsifiers) and unintentional compounds (e.g., bisphenol A, pesticides) are largely unstudied in regard to their effects on overall metabolic homeostasis. With that said, many of these contaminants have been found to dysregulate endocrine function, insulin signaling, and/or adipocyte function. Although momentum for the chemical obesogen hypothesis is growing, supportive, evidence-based research is lacking. In order to identify noxious synthetic compounds in the environment out of the thousands of chemicals that are currently in use, tools and models from toxicology should be adopted (e.g., functional high throughput screening methods, zebrafish-based assays). Finally, mechanistic insight into obesogen-induced effects will be helpful in elucidating their role in the obesity epidemic as well as preventing and reversing their effects.
Keywords: obesity, BPA, bisphenol A, food additives, preservatives, pesticides, plastics, pollutants, contaminants
Since the industrial revolution, the goals of food technology have predominately been maximizing palatability, optimizing process efficiency, increasing shelf life, reducing cost, and improving food safety (free from harmful viruses, bacteria, and fungi). As such, over 4,000 novel ingredients have entered the food supply, some intentionally (such as preservatives) and some inadvertently (such as bisphenol A, BPA), and there are 1,500 new compounds that enter the market every year . While food processing techniques are also constantly being optimized to minimize toxic compounds and toxicants such as lead, melamine, and aflatoxin, other “non-toxic” additives are not thoroughly tested for their chronic, additive, and/or cumulative effects on human physiology.
Obesity and related chronic disorders are increasing at alarming rates and it is estimated that 86% of Americans will be overweight by 2030 . This trend continues despite increases in awareness, nutritional and behavioral research, the amount of diet foods available, and even gym memberships . Unfortunately, the etiology of obesity and diabetes in regard to biochemical mechanisms is still largely not understood. Treatment and prevention of obesity hinges on our ability to 1) characterize the biochemical pathways that promote obesity, 2) identify what changes in our environment are promoting obesity, and 3) avoid and reverse the effects of the offensive agents and practices. It is crucial that clinicians understand and communicate that most novel food ingredients have not been evaluated for metabolic safety. In this review, we outline what agents have been identified that may be contributing to obesity, describe current methods being used to identify offensive compounds, and identify critical gaps in our methods and body of knowledge.
The importance of identifying agents that contribute to obesity
There is an abundance of research related to obesity etiology and prevention in regard to decreasing caloric intake and increasing energy expenditure. However, “non-traditional” risk factors are under increased scrutiny for their contributions to the obesity epidemic: emotional stress, sleep deprivation, disruption of normal circadian rhythm, composition of the gut microbiome, oxidative stress, medications such as antidepressants and oral contraceptives, average home temperature, and environmental toxicants [24••,36•,55]. Agents in our food supply have immense potential to affect metabolism due to continuous exposure and potential interactions among multiple compounds. A recently hypothesized factor contributing to the obesity epidemic is our exposure to obesogens, chemicals in our environment that can disrupt metabolism and lead to accumulation of excess fat mass (coined by Grün and Blumberg in 2006 ). It is critical that we identify these obesogens in our food supply in order to facilitate obesity prevention and treatment .
Unfortunately, many of the obesogenic compounds in our food supply were added deliberately to enhance production instead of being added to enhance nutrition. For example, pesticides are added to ward off insects during farming; BPA is a strong, clear plastic that has ideal properties for making bottles and coating cans; and mono- and diglycerides are added to emulsify the fat and water in foods to achieve a favorable texture. Simple exclusion of these compounds may not be possible until alternatives are developed, but then these novel compounds must be tested. Like pharmaceuticals, thorough testing is time-consuming and expensive.
Obesogen identification and characterization is in its infancy, and much of the scientific evidence supporting the relationship between synthetic compounds and the obesity epidemic is currently weak. Strong, evidence-based scientific support is derived from randomized, controlled trials, ideally cross-over design, that comprise four steps: 1) addition of the compound of interest, 2) observation of an effect, 3) removal of the compound of interest, and 4) disappearance of the effect. However, the bulk of evidence relating environmental contaminants and obesity is derived from epidemiological studies which are correlational by nature. While correlations are important, they are limited in that conclusions about causal relationships are impossible. Well-designed animal studies provide strong evidence within the animal model, but must be confirmed in humans. Cell studies are important for deriving mechanisms that may link certain compounds to obesity, yet provide only weak evidence for the global phenomenon (the obesity epidemic). Thus, we currently do not have any strong evidence that any contaminant, food additive, or ingredient that is “generally recognized as safe” (GRAS) causes obesity, which is essential for making confident recommendations and changes in public policy.
It is important to note that in evaluating foods for their contribution to obesity, we may identify ingredients that prevent obesity. For example, some hydrocolloids including guar gum and β-glucan may be able to increase satiety and reduce caloric intake with their bulking properties . Also, anthocyanins (potent color compounds from grapes, purple corn, blueberries, and other plants) may reduce oxidative stress, prevent obesity, and help control diabetes in cell culture, animal models, and humans . Again, not all compounds in a class are equal; for example, although the hydrocolloid guar gum may prevent obesity (mentioned above), another hydrocolloid called carrageenan, found commonly in chocolate milk and ice cream, may contribute to insulin resistance in mice .
What in our food is making us fat?
There are many aspects of the average Western diet that may promote obesity. The macronutrient ratio (fat:carbohydrate:protein), the characteristics of the fat (e.g., diets rich in palmitic acid vs. eicosapentaenoic acid), the characteristics of the carbohydrates (refined vs. whole grain carbohydrates) [2,59], and form of the protein  are major concerns and reviewed elsewhere [2,59-63]. In addition, advances in food processing have facilitated consumption of high caloric food that is low in other nutrients (e.g., edible oils, refined grains)  as well as increased the glycemic load of common meals . Increased consumption of nutrient-poor added fat, added sugar, added salt, and refined grains may also underlie obesity and co-morbidities in ways that extend beyond energy balance . Baillie-Hamilton announced a well-received hypothesis in 2002 highlighting the potential for environmental compounds in our food to contribute to the obesity epidemic . While the relationship between obesity and food structure is reviewed elsewhere [59-63], herein, we will focus on potential obesogens and obesity-promoting food additives in our foods supply (Table 1)......... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4101898/
|Posted on December 11, 2020 at 1:45 PM||comments (0)|
Olive oil contains dozens of phenolic compounds, each with its own unique health benefits. An advantage of these compounds is high bioavailability. Many kinds of research highlight the anti-inflammatory, antimicrobial, antibacterial and antiviral properties of these compounds.
Infections and infectious diseases are due to viruses, bacteria, parasites, fungi, and various pathogens. When the human body contracts an infection, it relies on the immune system to fight it. Although there are drugs for the treatment of infections, some foods of natural origin, such as olive oil, also provide good results in the prevention and treatment of infections.
In olive oil, there are several polyphenols with antibacterial properties against human pathogens, specifically hydroxytyrosol, and oleuropein, which have also shown to have antiviral properties.
A study, published in National Center for Biotechnology Information in 2019, established that the consumption of extra virgin olive oil promotes good intestinal health.
The fatty acids contained in olive oil
Fatty acids, also known as food lipids, contained in olive oil are involved in the modulation of the immune system and inflammatory processes. Therefore, they offer important anti-inflammatory benefits to prevent and treat various health conditions.
|Posted on December 11, 2020 at 1:45 PM||comments (0)|
Surgery is the mainstay therapy for HPV-induced laryngeal papillomatosis (LP) and adjuvant therapies are palliative at best. Research revealed that conjugated-linoleic acid (CLA) may improve the outcome of virally-induced diseases. The effects of Clarinol™ G-80 (CLA) and high oleic safflower oil (HOSF) on children with LP (concomitant with surgery) were evaluated.
A randomized, double-blinded, crossover and reference-oil controlled trial was conducted at a South African medical university. Study components included clinical, HPV type/load and lymphocyte/cytokine analyses, according to routine laboratory methods.
Overall: ten children enrolled; eight completed the trial; five remained randomized; seven received CLA first; all treatments remained double-blinded.
Children (4 to 12 years) received 2.5 ml p/d CLA (8 weeks) and 2.5 ml p/d HOSF (8 weeks) with a washout period (6 weeks) in-between. The one-year trial included a post-treatment period (30 weeks) and afterwards was a one-year follow-up period.
Main outcome measures
Changes in numbers of surgical procedures for improved disease outcome, total/anatomical scores (staging system) for papillomatosis prevention/viral inhibition, and lymphocyte/cytokine counts for immune responses between baselines and each treatment/end of trial were measured.
After each treatment all the children were in remission (no surgical procedures); after the trial two had recurrence (surgical procedures in post-treatment period); after the follow-up period three had recurrence (several surgical procedures) and five recovered (four had no surgical procedures). Effects of CLA (and HOSF to a lesser extent) were restricted to mildly/moderately aggressive papillomatosis. Children with low total scores (seven/less) and reduced infections (three/less laryngeal sub-sites) recovered after the trial. No harmful effects were observed. The number of surgical procedures during the trial (n6/available records) was significantly lower [(p 0.03) (95% CI 1.1; 0)]. Changes in scores between baselines and CLA treatments (n8) were significantly lower: total scores [(p 0.02) (95% CI −30.00; 0.00)]; anatomical scores [(p 0.008) (95% CI −33.00: -2.00)]. Immune enhancement could not be demonstrated.
These preliminary case and group findings pave the way for further research on the therapeutic potential of adjuvant CLA in the treatment of HPV-induced LP.
|Posted on December 11, 2020 at 1:40 PM||comments (0)|
Some free fatty acids derived from milk and vegetable oils are known to have potent antiviral and antibacterial properties. However, therapeutic applications of short to medium chain fatty acids are limited by physical characteristics such as immiscibility in aqueous solutions. We evaluated a novel proprietary formulation based on an emulsion of short chain caprylic acid, ViroSAL, for its ability to inhibit a range of viral infections in vitro and in vivo. In vitro, ViroSAL inhibited the enveloped viruses Epstein-Barr, measles, herpes simplex, Zika and orf parapoxvirus, together with Ebola, Lassa, vesicular stomatitis and SARS-CoV-1 pseudoviruses, in a concentration- and time-dependent manner. Evaluation of the components of ViroSAL revealed that caprylic acid was the main antiviral component; however, the ViroSAL formulation significantly inhibited viral entry compared with caprylic acid alone. In vivo, ViroSAL significantly inhibited Zika and Semliki Forest Virus replication in mice following the inoculation of these viruses into mosquito bite sites. In agreement with studies investigating other free fatty acids, ViroSAL had no effect on norovirus, a non-enveloped virus, indicating that its mechanism of action may be via surfactant disruption of the viral envelope. We have identified a novel antiviral formulation that is of great interest for prevention and/or treatment of a broad range of enveloped viruses.
The antimicrobial properties of fatty acids have been extensively reported in the literature (for review, see Thormar et al. (Thormar and Hilmarsson, 2007) and (Churchward et al., 2018). Previously, (Thormar et al., 1987) demonstrated the antiviral effects of 14 different free fatty acids and lipid extracts from human milk against vesicular stomatitis virus (VSV), herpes simplex virus (HSV) and visna virus revealed that short chain saturated fatty acids (butyric, caproic and caprylic) together with long chain saturated fatty acids (palmitic and stearic) had no or very little antiviral activity, whereas medium chain saturated entities including capric, lauric, myristic and long chain unsaturated oleic, linoleic and linolenic acids were anti-viral, albeit at different concentrations. Another study (Hilmarsson et al., 2005) reported similar trends in the antiviral activity of six medium chain fatty acids together with their alcohol and mono-glyceride derivatives against herpes simplex viruses 1 and 2. In contrast, Dichtelmuller et al (2002) reported that caprylic acid had antiviral activity against enveloped viruses including human immunodeficiency virus, bovine viral diarrhoea virus, Sindbis virus and pseudorabies virus (Dichtelmuller et al., 2002, Pingen et al., 2016). Studies investigating the antiviral properties of whole milk reported no antiviral properties of fresh human milk, whereas milk that had been stored at 4°C possessed potent antiviral activity against several viruses in vitro. Refrigeration disrupts the milk fat globule membrane allowing ingress of milk serum lipase which results in hydrolysis of milk fat triglyceride (Thormar et al., 1987, Isaacs et al., 1990). It was concluded that release of fatty acids from milk triglycerides in stored milk, and that recovered from neonatal (achlorhydric) stomachs, was responsible for generating antiviral factor(s) (Thormar et al., 1987).
We investigated the effect of a specifically formulated emulsion of free fatty acids, ViroSAL, on infectivity of enveloped and non-enveloped viruses. Caprylic acid delivered in the ViroSAL emulsion exhibited significant anti-viral effects. A range of enveloped viral infection systems was utilized, and complete inhibition of viral infection was observed without any evidence of cytotoxicity. ViroSAL had no effect on the infectivity of a non-enveloped virus, norovirus, which is in agreement with previous studies demonstrating that free fatty acids are ineffective against non-enveloped viruses (Thormar et al., 1987, Kohn et al., 1980). Furthermore, ViroSAL inactivated the enveloped mosquito-borne viruses Semliki Forest virus (SFV) and Zika virus (ZIKV) in vitro. Prophylactic topical treatment of viral infection in mosquito bites with ViroSAL inhibited local replication and dissemination of SFV and plasma levels of ZIKV in mice. Transmission electron microscopy analysis indicated that ViroSAL disrupts orf parapoxvirus envelope integrity, with higher concentrations completely disrupting virion morphology. These data indicate that ViroSAL has antiviral activity against a range of enveloped viruses in vitro and in vivo.
|Posted on December 11, 2020 at 1:35 PM||comments (0)|
Stubborn belly fat can make it hard to fit into your jeans and uncomfortable to carry around. Choosing to add monounsaturated fats into a balanced diet will help promote fat loss through your midsection. Include foods that are high in monounsaturated fats into your daily meal plan to help to burn unwanted fat.
VIDEO OF THE DAY
Burn Belly Fat
Belly fat can be banished when you fill your diet with monounsaturated fats. The March 2007 issue of the "Journal For Diabetes Care" explained that eating a source of monounsaturated fatty acids with each meal of your day will help your body burn fat from the stomach area. Monounsaturated fats help to increase your basal metabolic rate allowing your body to burn fat quicker.
The "American Journal of Clinical Nutrition" published a study in April 2009 that found eating monounsaturated fats increase satiety unlike saturated fats. Monounsaturated fats will help keep you full and satisfied longer. This will help prevent over-eating, which will help you restrict your calories for weight loss. Add olive oils to your pasta or avocados to your sandwich to help you include extra monounsaturated fats to your meals.
Almonds are a healthy source of monounsaturated fats. The Almond Board of California explains that including about 1 oz. of almonds daily will help to keep your metabolism elevated. Olive oil and avocado are also foods filled with monounsaturated fats. These fats will help you burn belly fat when eaten in moderation. Portion sizing is key because these foods can be high in calories. Limit the amounts you consume to 10 almonds or 1/2 an avocado for fat burning results.
Stubborn belly fat can be decreased when you incorporate exercise to your healthy eating plan. Cardio training most days of the week for 30 minutes will help you melt off body fat. Weight training should be done three days a week to increase your lean muscle, which will help your body burn more calories during the day. Also target training your midsection will help to whittle away your waistline.
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|Posted on December 11, 2020 at 1:25 PM||comments (0)|
Effects of Different Dietary Fatty Acids on Human Energy Balance, Body Weight, Fat Mass, and Abdominal Fat
Sze Yen Tan, in Nutrition in the Prevention and Treatment of Abdominal Obesity, 2014
The effects of increased MUFA intake on body weight and body composition were investigated using a within-subject crossover and a randomized controlled experimental design (Table 36.1). In one crossover study, 16 adults with type 2 diabetes mellitus (T2DM) received two test diets, one high in carbohydrate and another high in MUFA (from olive oil), for 3 months per diet (separated by a 1-month washout period). Total body fat mass decreased after the intervention periods but was not significantly different between the two diets. However, there appeared to be a trend of different fat mass loss patterns: participants lost upper body fat with the MUFA diet but gained upper body fat slightly during the high-carbohydrate diet. When examined as a ratio of upper-to-lower body fat mass, the high-carbohydrate diet induced a significantly higher ratio than the high-MUFA diet (P < 0.01) . A more recent crossover study that fed 11 insulin-resistant adults high-SFA, high-MUFA, and high-carbohydrate diets in a random order for 28 days each also failed to document additional effects of increased MUFA intake on body weight and fat mass loss. However, the MUFA-rich diet did prevent upper body fat accumulation that was induced by the high-carbohydrate diet. Consequently, the upper-to-lower body fat ratio was significantly higher in that diet group . Similar to the aforementioned studies, one study documented greater upper body fat loss after following a high-MUFA diet (vs. a high-SFA diet) for 4 weeks . This study also recorded significant losses in body weight and total body fat mass, which was not found in the other two studies. Differences in the study populations may explain the contradictory observations regarding total body fat mass loss: studies that included adults with T2DM or insulin resistance reported no additional benefits of MUFA on body weight and fat mass, while studies that recruited healthy male adults did. Impaired fatty acid oxidation has been previously reported in adults with T2DM [104,105].
The randomized controlled, parallel-arm studies that tested the effects of MUFA on body weight and body composition are limited, and were conducted using a weight loss paradigm. In one study, 57 overweight and obese adults were randomly assigned to follow a low-fat, high-protein (30% fat, 35% protein) or a high-fat, standard-protein (45% fat high in MUFA from mixed nuts and canola oil and 18% protein) diet . During the first 12 weeks of this trial, energy restriction was prescribed to promote weight loss; this was followed by an energy balance period of 4 weeks. This study did not find significant differences in body weight and fat mass loss between the two diets. The lack of effects of MUFA in this trial may be due to (1) the simultaneous manipulation of two dietary components (e.g. protein and fat); (2) the absence of a proper control group; (3) subtle acute physiological effects of MUFA that failed to translate into clinical observations; or (4) adaptation of the body to increased dietary MUFA during the study period. However, these possibilities are yet to be evaluated.
Another randomized controlled trial compared the weight- and fat-mass-reducing effects of a high-MUFA (from almonds) vs. a high-carbohydrate energy-restricted diet for 24 weeks . Like the previous study, the two intervention diets differed in more than one aspect: the MUFA diet contained higher total fat and lower carbohydrate (39% fat, 32% carbohydrate) than the high-carbohydrate diet (19% fat, 53% carbohydrate). In this study, greater reductions in weight (−18% vs. −11%), fat mass (−30% vs. 20%), and waist circumference (an indicator of abdominal fat; −14% vs. −9%) were observed in the high-MUFA group, although it should be pointed out that these superior clinical outcomes may not be attributable to MUFA alone. Almonds (the vehicle of MUFA used in this study) influence energy balance by promoting satiety [108,109] and dietary compensation [110–112], and the absorption of dietary fat from almonds is lower than previously thought . In summary, the presence of confounding factors in the intervention studies limits the ability to draw conclusions as to whether MUFA has therapeutic effects on body weight and total fat mass reduction. More longer-term and better-controlled intervention trials are therefore warranted.
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|Posted on December 11, 2020 at 1:10 PM||comments (0)|
OBJECTIVE— Central obesity is associated with insulin resistance through factors that are not fully understood. We studied the effects of three different isocaloric diets on body fat distribution, insulin sensitivity, and peripheral adiponectin gene expression.
RESEARCH DESIGN AND METHODS— Eleven volunteers, offspring of obese type 2 diabetic patients with abdominal fat deposition, were studied. These subjects were considered insulin resistant as indicated by Matsuda index values <4 after an oral glucose tolerance test, and they maintained A1C <6.5% without therapeutic intervention. All subjects underwent three dietary periods of 28 days each in a crossover design: 1) diet enriched in saturated fat (SAT), 2) diet rich in monounsaturated fat (MUFA) (Mediterranean diet), and 3) diet rich in carbohydrates (CHOs).
RESULTS— Weight, body composition, and resting energy expenditure remained unchanged during the three sequential dietary periods. Using dual-energy X-ray absorptiometry we observed that when patients were fed a CHO-enriched diet, their fat mass was redistributed toward the abdominal depot, whereas periphery fat accumulation decreased compared with isocaloric MUFA-rich and high-SAT diets (ANOVA P < 0.05). Changes in fat deposition were associated with decreased postprandial mRNA adiponectin levels in peripheral adipose tissue and lower insulin sensitivity index values from a frequently sampled insulin-assisted intravenous glucose tolerance test in patients fed a CHO-rich diet compared with a MUFA-rich diet (ANOVA P < 0.05).
CONCLUSIONS— An isocaloric MUFA-rich diet prevents central fat redistribution and the postprandial decrease in peripheral adiponectin gene expression and insulin resistance induced by a CHO-rich diet in insulin-resistant subjects.
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|Posted on December 11, 2020 at 1:05 PM||comments (0)|
Safflower oil have been reviewed for nutraceutical applications.
Good stability index allows encapsulation of safflower oil in functional foods.
Recently extraction techniques of safflower oil have been reviewed.
Summary of recent findings related to bone health is reviewed.
Applications of safflower oil towards functional foods development is reviewed.
Safflower is a multiple purpose crop generally grown for oil production. The safflower oil is considered to be a better oil since it contains higher amount of oleic and linoleic acids than other oil seed crops. Safflower oil has numerous applications in food, cosmetics, pharmaceutical and feed industry. An added advantage of safflower oil is lower cost of production thus can become an alternate option for those who cannot afford to buy olive and other functional oils.
Scope and approach
This manuscript provides a comprehensive review on critical aspects of pharmacological and nutritional applications of safflower oil. A higher antioxidant activity renders better stability of safflower seed oil over extended storage period. Moreover, a higher content of omega six fatty acids makes it a healthier choice for consumption especially where olive oil being the only but costly choice. There has been a surge in developing innovative and efficient methods to extract safflower oil including super critical fluid and enzymatic extraction techniques.
Key findings and conclusions
A higher stability index makes it possible to encapsulate safflower oil or used it as a carrier in bioactive functional ingredient delivery systems. The functional properties of safflower oil can be used to treat skin infections, bone related disorders, menopause and atherosclerosis. Composition and distribution of phenolic contents of safflower oil has not been explored to its full potential. There is a need to conduct exclusive research on exploring the role of phenolic compounds in food and pharma industrial applications.
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|Posted on December 11, 2020 at 1:05 PM||comments (0)|
FDA Approves New Qualified Health Claim for Oils High in Oleic Acid
That Cut Risk of Coronary Heart Disease
The FDA has determined that there's credible evidence to support a qualified health claim that consuming oleic acid in edible oils, such as olive oil, sunflower oil, safflower oil, canola oil, or soybean oil, may reduce the risk of coronary heart disease.
After conducting a systematic review of the available scientific evidence, the FDA now intends to exercise enforcement discretion over the use of two qualified health claims characterizing the relationship between consumption of oleic acid in edible oils (containing at least 70% of oleic acid per serving) and reduced risk of coronary heart disease. Oleic acid is a monounsaturated fat which, when substituted for fats and oils higher in saturated fat, may reduce the risk of coronary heart disease.
The science behind the new qualified health claim for oleic acid, while not conclusive, is promising. The FDA evaluated results from seven small clinical studies that evaluated the relationship between consumption of oils containing high levels of oleic acid (at least 70% per serving) and improved cholesterol levels, which indicates a reduced risk of coronary heart disease. Six of the studies found that those who were randomly assigned to consume diets containing oils with high levels of oleic acid as a replacement to fats and oils higher in saturated fat experienced a modest lowering in their total cholesterol and heart-damaging LDL cholesterol levels compared with those who ate a more Western-style diet that was higher in saturated fat. One study showed no significant effect. Importantly, and as noted in the health claim, none of the studies found that eating oleic acid-containing oils had beneficial heart effects unless they replaced other types of fats and oils higher in saturated fats in the diet.
The FDA intends to exercise enforcement discretion for the following qualified health claims:
"Supportive but not conclusive scientific evidence suggests that daily consumption of about 1½ tablespoons (20 grams) of oils containing high levels of oleic acid, when replaced for fats and oils higher in saturated fat, may reduce the risk of coronary heart disease. To achieve this possible benefit, oleic acid-containing oils should not increase the total number of calories you eat in a day. One serving of [x] oil provides [x] grams of oleic acid (which is [x] grams of monounsaturated fatty acid)."
"Supportive but not conclusive scientific evidence suggests that daily consumption of about 1 1/2 tablespoons (20 grams) of oils containing high levels of oleic acid may reduce the risk of coronary heart disease. To achieve this possible benefit, oleic acid-containing oils should replace fats and oils higher in saturated fat and not increase the total number of calories you eat in a day. One serving of [x] oil provides [x] grams of oleic acid (which is [x] grams of monounsaturated fatty acid)."
The qualified health claims respond to a petition filed by Corbion Biotech, Inc. Qualified health claims are supported by credible scientific evidence, but don't meet the more rigorous "significant scientific agreement" standard required for an authorized FDA health claim. As such, they must be accompanied by a disclaimer or other qualifying language so that the level of scientific evidence supporting the claim is accurately communicated. The FDA's intent to exercise enforcement discretion for the use of the qualified health claims means that the agency doesn't intend to object to its use, as long as the products bearing the claim are consistent with the factors FDA stated in the Letter of Enforcement Discretion that responds to the petition.
Oleic acid can be found naturally in numerous food sources, including edible oils, meat (such as beef, chicken, and pork), cheese, nuts, sunflower seeds, eggs, pasta, milk, olives, and avocados. Corbion Biotech's petition identified the following edible oils that contain at least 70% of oleic acid per serving: 1) high oleic sunflower oil, 2) high oleic safflower oil, 3) high oleic canola oil, 4) olive oil, and 5) high oleic algal oil.
— Source: FDA
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|Posted on December 4, 2020 at 5:50 PM||comments (0)|
Background: This study has been done to analyze the effect of nutritional elements on human immune system. Human body possesses many elements in order to protect itself. In the simplest term, the outer creatine layer on the skin is one of them. Human immune system, along with the cells in peripheries circulation, hormones and solvable immuno modulators is fairly sophisticated and had yet not been resolved completely. Immune system, in human organism detects the molecules which are unfamiliar to its own structure and responds to them in convenient terms. In the event of pathogen factor entrance into human body, immune system steps in to action and creates immune response.
There are many factors that affect immune system functions, one of those is nutrition. There is a significant correlation between immune system and nutrition, furthermore malnutrition shouldn’t be considered as energy and a protein deficiency alone. Due to these reasons, the main aim of nourishment is not merely to gain energy and protein, but to enhance resistance against ailments with some specific nutriment and to turn the inflammatory response in someone’s best interests. The nutriments which show beneficial effects on immune system are called. Immune nutriments and nourishment on these nutriments is called immune diet. The main fields of application of immune diet is
patient undergoing surgery, traumatized, cancer patients, patients who need intensive care and patients with serious infections such as sepsis.
Conclusions: In conclusion, in order to strengthen our immune system, to reduce the risks of ailments and to stay healthy the body defence system in our body should be strengthened. To do so, particular costly medicines can be used; however, regular exercises and having an immune diet will be more economical and natural preference.
Nourishment; Immune system; Nutritional elements; Immunological nourishment
Human beings are in close relation with the microorganisms that were common in nature. Immune system is a means of protection against the damaging effects of noxas, which cause infection in our bodies. Immune system is a form of protection consisting of, thymus, spleen, lymph nodes and some specific immunity cells .
Immunity, on resistance against microorganisms acts both naturally and acquired in a complex mechanism, but they are mostly in collaboration. One of the factors that affect natural resistance is nutrition. Malnutrition breaks down the immune functions by suppressing the immune system .
The dietary factors that cause harm to immunity functions are either deficient intake of macro-nutrient elements (fat, carbohydrate, protein) or deficiency in some specific micronutrient elements (vitamin, mineral, water). Balanced nutrition, especially in terms of adequate vitamin, mineral and protein intake, enhances the resistance against infections. Research’s show that balanced nutrition subsidizes the immune system and Cary out vital importance on the system .
Nutrition has an impact on body resistance and microbes. Excessive strain, Traumas, Ambustions, etc., could cause protein destruction consequently body resistance decreases. Malnutrition, especially in childhood play vital role in catching illness and mortality. Malnutrition paves the way for infections and their complications. This composed infection distorts the nutrition and abates the immunity [2,3].
The effects of nutritional elements on immune system has been a study case for many research’s because there is significant influence on supporting immune system and in deficiency it causes malfunction in immune system [2,3].
Immune system is a common name for structures within our bodies that protects living organisms against harmful substances. Human body possesses many elements in self defence. One of the simplest of those is outer creatine layer on the skin. Another element is biochemical body units .
The substance that stimulates the immune system is generally known as nonspecific substance like macrophage and neutrophils that enhance the defence capability of phagocytes. The many of those substances ad here the surfaces of phagocytes and lymphocyte cells and also stimulates the production of interferon, interleukin and sophisticated compositions, consequently activates the immune system .
Immune system has a structure that consists of similar neurologic system. One of the most significant traits of immune system is, having the ability of recognizing the millions of different threats and distinguishes them. Thanks to this trait, the functionary cells in immune system, detect the unfamiliar object, memorise it and recognise it when coming across later.
These structures are; thymus spleen, lymph nodes and specific immunity cells. Immune system gets down to work as soon as pathogenic factors entering the body. This defence carried out by immune system against pathogenic called “immune response” [1,5,6].
Immune system is a moliminous mechanism in fighting against diseases and sanitation. The possible response of immune system against body cells is called autoimmune reactions and consequently autoimmune disorders occur ...... https://www.omicsonline.org/open-access/the-effect-of-nutritional-elements-on-the-immune-system-2165-7904.1000152.php?aid=10186
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|Posted on December 4, 2020 at 5:45 PM||comments (0)|
Diet and Immune Function
Caroline E. Childs,1 Philip C. Calder,1,2 and Elizabeth A. Miles1,*
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
A well-functioning immune system is critical for survival. The immune system must be constantly alert, monitoring for signs of invasion or danger. Cells of the immune system must be able to distinguish self from non-self and furthermore discriminate between non-self molecules which are harmful (e.g., those from pathogens) and innocuous non-self molecules (e.g., from food). This Special Issue of Nutrients explores the relationship between diet and nutrients and immune function. In this preface, we outline the key functions of the immune system, and how it interacts with nutrients across the life course, highlighting the work included within this Special Issue. This includes the role of macronutrients, micronutrients, and the gut microbiome in mediating immunological effects. Nutritional modulation of the immune system has applications within the clinical setting, but can also have a role in healthy populations, acting to reduce or delay the onset of immune-mediated chronic diseases. Ongoing research in this field will ultimately lead to a better understanding of the role of diet and nutrients in immune function and will facilitate the use of bespoke nutrition to improve human health.
Keywords: nutrition, immunity, macronutrients, micronutrients, microbiome, life course, probiotic, prebiotic, inflammation
1. Overview of the Immune System
Broadly, cells of the immune system may be divided into those of the innate and those of the adaptive immune response. The innate response is the first response to an invading pathogen. Cells of the innate immune response include phagocytes (e.g., macrophages and monocytes), neutrophils, dendritic cells, mast cells, eosinophils, and others. The innate response is rapid, but not specialised and is generally less effective than the adaptive immune response.
The adaptive immune response has the ability to specifically recognise a pathogen and ‘remember’ it if exposed to it again. T cells are critical in antigen recognition and the co-ordination of the immune response. T cells are present in an array of subtypes that coordinate different types of immune responses. Broadly, they are divided into the cytotoxic T cells (bearing the CD8 receptor), which are involved in direct killing of infected damaged cells and tumour cells, and the T helper cells. T helper (Th) cells bear the CD4 receptor and are important in coordinating the responses of other immune cells. There are a number of subtypes of Th cells, defined by the cytokines they produce. Initial studies identified two subsets, the Th1 cells, which produced interferon gamma (IFN-γ) and interleukin (IL)-2 and were important in antiviral and cellular immune responses, and the Th2 subset producing IL-4, IL-5, and IL-13 and involved in humoral (antibody) and anti-parasitic responses (but also in allergic responses) . It is now apparent that there are a number of other Th subtypes, which do not fall into these categories. This includes Th17 cells, which produce IL-17A, IL-17F, and IL-22 and are important in fighting extracellular pathogens (bacteria and fungi) . There are also T regulatory cells (Treg), which are CD4-bearing T cells vital in maintaining immune tolerance to allow the immune system to ignore non-harmful non-self (such as food, pollen, and environmental antigens such as latex). Thus, the role of T cells is coordinating an appropriate immune response following immune stimulation or challenge.
The other lymphocytes of the adaptive immune system are the B cells, which are responsible for antibody or immunoglobulin (Ig) production. Like T cells, B cells respond specifically to an antigen. They can differentiate into short-lived plasma cells, which produce Igs in the short term, or can become long-lived plasma cells. Igs are pathogen-specific molecules, which help the immune system to recognise and destroy pathogens. The B cells can differentiate into plasma cells, which produce one of five classes of Ig (IgM, IgD, IgG, IgA, and IgE). Each class of Ig has a specialised role . IgM is the first Ig expressed during development, is often found as a multimeric molecule (e.g., pentameric), and can bind an antigen to identify it for destruction by immune cells. IgD is found in low concentrations in the plasma and the specialist role of IgD is not yet clear. IgG is the predominant Ig class and can persist for long periods. It has important roles in antigen labelling, resulting in more effective removal. IgA can be found in the serum (mostly as a monomer) and at mucosal surfaces (normally as a dimer). At the mucosal surface, IgA protects against bacteria and or viruses, preventing infection. IgA also has an important role in neutralising food antigens and helping to maintain immune tolerance to food antigens (preventing the development of food allergy) . IgE has a role in clearance of extracellular parasites (e.g., helminths) but when produced inappropriately to innocuous environmental and food antigens, has an important role in IgE-mediated allergy. B cells go through a process called class switching to set the class of Ig that the plasma cells derived from them will produce. B cell class switching is controlled by the cytokines present, particularly IL-4, IL-6, and IFN-γ secreted from Th cells .
T and B cells can specialise to become memory cells, which persist permanently or for very long periods and are able to recognise the antigen if encountered again and elicit a rapid, pathogen-specific immune response.
The effective deployment of the immune system against pathogens or harmful signals and the swift resolution of the immune response is required for survival. The fighting of infection is only one piece of the puzzle. A fulminating immune response is costly in terms of energy expended and results in damage to the host tissues; thus, rapid and complete resolution of an immune response is also key. Cytokines play a role in resolution of immune responses. IL-10, which is produced by a range of immune cells including Tregs, has anti-inflammatory actions including suppressing inflammatory cytokine production .
The instigation of an immune response and the activities of the immune cells results in inflammation (seen as redness, swelling, and the feeling of heat and pain), which are signs of the damage to the tissue going on whilst the immune system does its work. This is an expected outcome of an effective immune response. Increasingly there is concern that modern lifestyle changes have resulted in the promotion of ongoing, low-grade, whole-body (systemic) inflammation caused by immune and other cells (e.g., adipocytes, the cells that store lipids in fat tissue) . Such exposures may include diet quality and quantity .
2. The Role of Nutrition in Immune Function
Adequate and appropriate nutrition is required for all cells to function optimally and this includes the cells in the immune system. An “activated” immune system further increases the demand for energy during periods of infection, with greater basal energy expenditure during fever for example. Thus, optimal nutrition for the best immunological outcomes would be nutrition, which supports the functions of immune cells allowing them to initiate effective responses against pathogens but also to resolve the response rapidly when necessary and to avoid any underlying chronic inflammation. The immune system’s demands for energy and nutrients can be met from exogenous sources i.e., the diet, or if dietary sources are inadequate, from endogenous sources such as body stores. Some micronutrients and dietary components have very specific roles in the development and maintenance of an effective immune system throughout the life course or in reducing chronic inflammation. For example, the amino acid arginine is essential for the generation of nitric oxide by macrophages, and the micronutrients vitamin A and zinc regulate cell division and so are essential for a successful proliferative response within the immune system.
Undernutrition is well understood to impair immune function, whether as a result of food shortages or famines in developing countries, or as a result of malnutrition arising from periods of hospitalisation in developed countries. The extent of impairment that results will depend upon the severity of the deficiency, whether there are nutrient interactions to consider, the presence of infection, and the age of the subject . A single nutrient can also exert multiple diverse immunological effects, such as in the case of vitamin E, where it has a role as both antioxidant, inhibitor of protein kinase C activity, and potentially interacting with enzymes and transport proteins . For some micronutrients, excessive intake can also be associated with impaired immune responses. For example, supplementation with iron can increase morbidity and mortality of those in malaria endemic regions. As well as nutrition having the potential to effectively treat immune deficiencies related to poor intake, there is a great deal of research interest in whether specific nutrient interventions can further enhance immune function in sub-clinical situations, and so prevent the onset of infections or chronic inflammatory diseases.
3. Gut-Associated Lymphoid Tissue
The majority of immune cells within the human body are found within the gut-associated lymphoid tissue (GALT), reflecting the importance of this immune tissue in maintaining host health. In ingesting food, we expose ourselves to near constant and massive antigenic stimulation, and our immune system must be able to provide strong and protective immunity against invasive pathogens, while tolerating food proteins and commensal bacteria. In order to achieve this, the GALT contains a variety of sensing and effector immune functions. Dendritic cells and M cells sample the gut content, while plasma B cells within the lamina propria produce IgA, providing protection against pathogenic organisms. Specialised immune regions known as Peyer’s patches, rich in immune cells, allow for communication between immune cells resident within the GALT, propagation of signals to the wider systemic immune system, and the recruitment or efflux of immune cells .
Within the gut lumen itself, the human gut microbiome will provide antigens and signals with the potential to interact with resident and systemic immune cells. The composition of the gut microbiome changes over the life course, in response to dietary components, and to environmental factors such as antibiotic exposure. Dietary interventions targeted at the gut microbiome include probiotics and prebiotics. Probiotics are defined as “live microorganisms, which, when consumed in adequate amounts, confer a health benefit of the host”  while prebiotics, “a substrate that is selectively utilized by host microorganisms conferring a health benefit” , tend to be non-digestible oligosaccharides such as fructo-oligosaccharides and galacto-oligosaccharides. Provision of plant-based diets may enhance the diversity of nutrients that reach the gut microbiome, with the indigestibility of plant cell walls enabling peptides and lipids, which may otherwise have been absorbed in the upper digestive tract to reach the microbiome . There may be circumstances in which immune cells of the GALT come into direct contact with nutrients or gut microbiota, such as in the case of reduced epithelial integrity, or ‘leaky gut’ observed in both acute and chronic gut inflammation . Such changes in gut permeability may be influenced by micronutrient status such as that of vitamin D .
A number of nutrients and dietary interventions have demonstrated the capacity to improve measures of gut health or to reduce gut inflammation. Protein hydrolysates have been demonstrated to enhance barrier function and IgA production in animal models, and as a result may have applications for incorporation within hypo-allergenic infant formula and clinical nutrition for those with conditions such as inflammatory bowel disease . Animal models of gut inflammation have identified that providing probiotic bacteria can reduce inflammation, with reductions in proinflammatory Th1 and Th17 cytokines such as IL-17 and IFN-γ, and enhanced production of inflammation resolving cytokine IL-10 . Prebiotics can also enhance barrier function, in addition to their role as substrates for bacterial metabolism . Santiago-Lopez et al. have investigated the effect of fermented milk on a murine model of inflammatory bowel disease  and demonstrated a reduction in serum IL-17 and IFN-γ following fermented milk consumption when compared with the control group.
4. Immune Function Over the Life course
The developing foetus and neonates have an immature immune system, with poor antibody production and a low proliferative response to challenge. In utero, the foetus can gain passive protection from its mother via antibodies, which cross the placenta. This is the basis by which infants in the UK are provided with early protection against whooping cough, with mothers offered vaccination in their third trimester, in order to provide passive immunity to their infants until they reach the age of infant vaccinations. While immature, the foetal immune system can produce antibodies, and allergens can reach the developing foetus, and allergen-specific IgE can be detected in cord blood samples . Another signature of the immaturity of the immune system in early life is the susceptibility of neonates to infections, and the associated higher burden of morbidity and mortality.
The development of the immune system in early life will be influenced by both feeding practices and environmental exposures. Breastfeeding provides further passive immunity to the infant, for example via transfer of antibodies and cytokines. Breast milk components can also stimulate maturation of the gut-associated lymphoid tissue, with breast milk known to be rich in bifidogenic oligosaccharides and to contain its own unique microbiota. Human milk oligosaccharides (HMOs) are synthesised from lactose in the mammary gland, and the specific HMO profile will vary between individuals and across contexts and changes over the time course of lactation . These HMOs have been found to confer health benefits to infants by inhibiting the adhesion of microorganisms to the intestinal mucosa, enhancing the production of short-chain fatty acids by bacteria within the microbiome, and inhibiting inflammation . Other immune active components of breast milk are also likely to be involved in immune system maturation, with studies identifying that the growth factors epidermal growth factor, fibroblast growth factor 21, and transforming growth factor-β2 can change lymphocyte phenotypes in new-born rats when provided as supplements by oral gavage .
In infancy, diverse environmental factors will impact upon immune system development; identified factors include pet ownership, antibiotic use, and the timing of introduction of foods . The opportunity for introduction of prebiotic oligosaccharides during the introduction of foods has been explored, with the suggestion that this could provide a unique opportunity to influence the developing microbiome and thereby interact with the developing immune system . These early years of life are a critical period in the development of the immune system, particularly for T cell function, with the thymus maturing and reaching its maximum size relative to body weight in infancy .
As we move through the life course towards later life, a decline in immune function is observed among older adults. As was the case in infancy, older adults are more susceptible to infections, and have more serious complications as a result than younger people. This declining immune function is known as immunosenescence and reflects deterioration of both the acquired and innate immune systems . Declining T cell function with age arises from thymic involution and decreased thymic output, resulting in fewer naive T cells and more memory cells in the circulation . Ageing is also associated with increased inflammation in the absence of infection and has been found to predict hospitalisation and death . A number of micronutrient deficiencies have been identified as contributors to such declining immunity, and so may provide opportunities for targeted interventions to restore immune function .
5. Chronic Systemic Inflammation
Chronic systemic inflammation is a key underlying feature for a range of chronic non-communicable disease conditions such as cardiovascular disease, stroke, and autoimmune disorders such as rheumatoid arthritis. This chronic inflammation is positively correlated with aging and other co-morbidities (e.g., obesity, cardiovascular disease, insulin resistance). Interestingly, in a study in healthy adults, increasing age was found to be a risk factor for chronic systemic inflammation, independent of other risk factors such as body mass index, blood pressure, and blood lipid profiles .
The rising worldwide prevalence of obesity in children and adults is of grave concern. Obesity and over nutrition are strongly associated with chronic inflammation, metabolic perturbation, and higher risk for a number of chronic diseases including cardiovascular disease, stroke, type 2 diabetes mellitus, and chronic liver disease. This metabolism-induced inflammation associated with obesity is termed metaflammation, and the Western diet is a known risk factor [31,32]. The Western diet is characterised by a diet high in sugar, trans and saturated fats, but low in complex carbohydrates, fibre, micronutrients, and other bioactive molecules such as polyphenols and omega 3 polyunsaturated fatty acids. The mechanisms by which the Western diet predispose individuals to metaflammation are still under investigation. However, one mechanism which has been reported is the increased uptake of lipopolysaccharide (LPS, a constituent of gram-negative bacterial cells walls), from microbes in the gut because of increased gut leakiness. This LPS is sensed by cells of the innate immune system through toll-like receptor 4 (TLR4). Activation of TLR4 by LPS will induce an inflammatory response by the immune cells. Certain nutrients, notably long-chain omega 3 polyunsaturated fatty acids, can interfere with TLR4 activation and, thus, can ameliorate this inflammatory signal. Rogero et al. describe the relationship between obesity and inflammation and explores the immune pathway for this mechanism and the anti-inflammatory roles of omega 3 fatty acids in this process .
Interestingly, in juxtaposition with the review by Rogero et al. on inflammation in obesity, Dalton and colleagues report a study into systemic inflammation in individuals with the serious psychological eating disorder, anorexia nervosa . They show that in a severely undernourished state, there are indications of systemic inflammation with an increased serum concentration of IL-6 when compared with healthy control participants. IL-6 is a classically inflammatory cytokine produced by immune and other cells. Whether this inflammation is the result of the impact of undernutrition or whether the clinical condition is the result of pre-existing inflammation is a matter that remains to be determined. It has been shown that patients with clinical depression have increased systemic inflammation suggesting that inflammation may have a bearing on mental health and wellbeing .
In contrast with the Western diet, the Mediterranean diet is rich in vegetables, fruit, nuts, legumes, fish, and ‘healthy’ dietary fats. The Mediterranean diet is associated with a reduced risk of chronic disease such as cardiovascular disease, cancer, and more recently Alzheimer’s disease . A range of bioactive compounds found in fruits and vegetables have been reported to offer one explanation for the protective effect of diets rich in fruits and vegetables (e.g., Mediterranean diet) on the reduction of risk for developing non-communicable diseases attributed to chronic inflammation (e.g., cardiovascular disease). One family of molecules, which are known to have a role in regulation of inflammation are the dietary polyphenols . Yahfoufi et al. explain the mechanisms by which polyphenols can be immunomodulatory and anti-inflammatory and explore the evidence for the role of dietary polyphenols in reducing the risk of cardiovascular disease, some neurological diseases, and cancer .
6. Nutrition in the Clinical Setting
In clinical settings, acute inflammation may be a sudden, severe, and overwhelming process. If not controlled, this severe systemic inflammation results in sepsis, culminating in multiple organ failure and death. Sepsis is a major global cause of death killing approximately 6 million people per year and is estimated to be the cause of 30% of neonatal deaths . In this Special Issue of Nutrients, the role of zinc in sepsis is discussed . Zinc is known to be an important micronutrient for the immune system. It has a role as a cofactor with both catalytic and structural roles in many proteins . Even a mild deficiency in zinc has been associated with widespread defects in both the adaptive and innate immune response . During sepsis, zinc homeostasis is profoundly altered with zinc moving from the serum into the liver. Alker and Haase consider this phenomenon and the implications for therapeutic options to improve outcomes in patients presenting with sepsis .
Selenium is a trace element that, like zinc, has critical functional, structural, and enzymatic roles, in a range of proteins. Poor selenium status is associated with a higher risk for range of chronic diseases including cancer and cardiovascular disease . In addition to critical roles in many non-immune tissues within the body, selenium is important for optimal immune function. Avery and Hoffman explain the role of selenium in immunobiology and the mechanisms by which selenoproteins regulate immunity. The evidence for the significance of selenium status in infectious diseases including human immunodeficiency virus infection is reviewed .
Glutamine is a nonessential amino acid that provides an important energy source for many cell types including those involved in immune responses. It also serves as a precursor for nucleotide synthesis, particularly relevant for rapidly dividing cells such as the immune cells during an immune response. During infection, the rate of glutamine consumption by immune cells is equivalent or greater than that for glucose. Glutamine has roles in the functions of a number of immune cells including neutrophils, macrophages, and lymphocytes . In catabolic conditions (e.g., infection, inflammation, trauma), glutamine is released into the circulation, an essential process controlled by metabolic organs such as the liver, gut, and skeletal muscles. Despite this adaptation, a significant depletion of glutamine is seen in the plasma and tissues in critical illness, which has provided a rationale for the use of in clinical nutrition supplementation of critically ill patients. How glutamine homeostasis is maintained and when and how to utilise glutamine in the clinical setting is explored in a review by Cruzat et al. .
The vitamin D receptor (VDR) is a nuclear receptor that can directly affect gene expression . The presence of VDR in the majority of immune cells immediately suggests an important role for this micronutrient in immune cell activities . Furthermore, vitamin D-activating enzyme 1-α-hydroxylase (CYP27B1), which results in the active metabolite 1 α,25-dihydroxyvitamin D3 (1,25(OH)2D3), is expressed in many types of immune cells. Ligation of VDR by 1,25(OH)2D3 can elicit the production of antimicrobial proteins and influence cytokine production by immune cells [47,48]. Sassi, Tamone, and d’Amelio have reviewed the evidence for the role of the nutrient vitamin D in the innate and adaptive immune systems .
In this Special Issue of Nutrients, the collected works provide a breadth of reviews and research indicating the key influence of nutrients and nutrition on immune responses in health and disease and across the life course. Nutrients may impact directly or indirectly upon immune cells causing changes in their function or may exert effects via changes in the gut microbiome. A better understanding of the role of nutrients in immune function will facilitate the use of bespoke nutrition to improve human health.
|Posted on December 4, 2020 at 5:45 PM||comments (0)|
Neighborhood Disparities in Access to Healthy Foods and Their Effects on Environmental Justice
Angela Hilmers, MD, MS,corresponding author David C. Hilmers, MD, MPH,corresponding author and Jayna Dave, PhD
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Environmental justice is concerned with an equitable distribution of environmental burdens. These burdens comprise immediate health hazards as well as subtle inequities, such as limited access to healthy foods.
We reviewed the literature on neighborhood disparities in access to fast-food outlets and convenience stores. Low-income neighborhoods offered greater access to food sources that promote unhealthy eating. The distribution of fast-food outlets and convenience stores differed by the racial/ethnic characteristics of the neighborhood.
Further research is needed to address the limitations of current studies, identify effective policy actions to achieve environmental justice, and evaluate intervention strategies to promote lifelong healthy eating habits, optimum health, and vibrant communities.
ENVIRONMENTAL JUSTICE HAS been defined as
fair treatment and meaningful involvement of all people regardless of race, ethnicity, income, national origin, or educational level in the development, implementation, and enforcement of environmental laws, regulations, and policies.1(p1)
Fair treatment signifies that “no population, due to policy or economic disempowerment, is forced to bear a disproportionate exposure to and burden of harmful environmental conditions.”1(p1) The concept of environmental justice, which has its roots in the fight against toxic landfills in economically distressed areas, can be similarly applied to the inequitable distribution of unhealthy food sources across socioeconomic and ethnic strata.1 The neighborhood environment can help promote and sustain beneficial lifestyle patterns or can contribute to the development of unhealthy behaviors, resulting in chronic health problems among residents.2–4 The higher prevalence of obesity among low-income and minority populations has been related to their limited access to healthy foods5–18 and to a higher density of fast-food outlets and convenience stores where they live.9,19–21 These environmental barriers to healthy living represent a significant challenge to ethnic minorities and underserved populations and violate the principle of fair treatment.
Several studies have investigated disparities in the distribution of neighborhood vegetation,22,23 the proximity of residences to playgrounds,24 and the accessibility of supermarkets and grocery stores,25,26 but fewer have examined access to fast-food outlets and convenience stores as a function of neighborhood racial and socioeconomic demographics. To our knowledge, our review is the first to expand the focus of environmental justice from environmental hazards and toxic exposures to issues of the food environment by examining research on socioeconomic, ethnic, and racial disparities in neighborhood access to fast-food outlets and convenience stores.
We reviewed studies of differences in accessibility of fast-food outlets and convenience stores by the socioeconomic and racial/ethnic characteristics of neighborhoods. With the assistance of an experienced health science librarian, we conducted searches in the MEDLINE, PubMed, PsycINFO, EBSCO Academic Search Premier, and Scopus databases. Key words were “neighborhood deprivation,” “food environment,” “food sources,” “fast-food restaurants,” “convenience stores,” “bodegas,” “disparity,” “inequality,” “minorities,” “racial/ethnic segregation,” and “socioeconomic segregation.” We included only original, peer-reviewed studies published in English between 2000 and 2011. Comments, editorials, dissertations, conference proceedings, newsletters, and policy statements were excluded. We also excluded studies that focused on methods and measurements, did not examine socioeconomic or racial/ethnic characteristics of the neighborhood, or used schools as a proxy for neighborhood environment.
Our search identified 501 unique citations; after detailed inspection, we selected 24. The primary reasons for exclusion were irrelevant outcomes or comparisons (n = 316), focus on dietary behavior (n = 96), and methodology studies (n = 65). We defined fast-food outlets as
take-away or take-out providers, often with a ‘drive-thru’ service which allows customers to order and pick up food from their cars; but most also have a seating area in which customers can eat the food on the premises (http://www.merriam-webster.com).
Examples of fast-food outlets were fast-food restaurant chains, take-away or carry-out establishments, and small local fast-food businesses. We defined convenience stores as
retail stores that sell a combination of gasoline, fast foods, soft drinks, dairy products, beer, cigarettes, publications, grocery items, snacks, and nonfood items and have a size less than 5000 square feet.27(p996) .......... https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482049/
Indexed for National Institute Of Health by Dragonfly Kingdom Library
|Posted on November 29, 2020 at 3:50 PM||comments (0)|
What are triglycerides?
Triglycerides are a type of fat (lipid) found in your blood.
When you eat, your body converts any calories it doesn't need to use right away into triglycerides. The triglycerides are stored in your fat cells. Later, hormones release triglycerides for energy between meals.
If you regularly eat more calories than you burn, particularly from high-carbohydrate foods, you may have high triglycerides (hypertriglyceridemia).
What's considered normal?
A simple blood test can reveal whether your triglycerides fall into a healthy range:
Normal — Less than 150 milligrams per deciliter (mg/dL), or less than 1.7 millimoles per liter (mmol/L)
Borderline high — 150 to 199 mg/dL (1.8 to 2.2 mmol/L)
High — 200 to 499 mg/dL (2.3 to 5.6 mmol/L)
Very high — 500 mg/dL or above (5.7 mmol/L or above)
Your doctor will usually check for high triglycerides as part of a cholesterol test, which is sometimes called a lipid panel or lipid profile. You'll have to fast before blood can be drawn for an accurate triglyceride measurement.
What's the difference between triglycerides and cholesterol?
Triglycerides and cholesterol are different types of lipids that circulate in your blood:
Triglycerides store unused calories and provide your body with energy.
Cholesterol is used to build cells and certain hormones.
Why do high triglycerides matter?
High triglycerides may contribute to hardening of the arteries or thickening of the artery walls (arteriosclerosis) — which increases the risk of stroke, heart attack and heart disease. Extremely high triglycerides can also cause acute inflammation of the pancreas (pancreatitis).
High triglycerides are often a sign of other conditions that increase the risk of heart disease and stroke, including obesity and metabolic syndrome — a cluster of conditions that includes too much fat around the waist, high blood pressure, high triglycerides, high blood sugar and abnormal cholesterol levels.
High triglycerides can also be a sign of:
Type 2 diabetes or prediabetes
Metabolic syndrome — a condition when high blood pressure, obesity and high blood sugar occur together, increasing your risk of heart disease
Low levels of thyroid hormones (hypothyroidism)
Certain rare genetic conditions that affect how your body converts fat to energy
Sometimes high triglycerides are a side effect of taking certain medications, such as:
Estrogen and progestin
Some HIV medications
What's the best way to lower triglycerides?
Healthy lifestyle choices are key:
Exercise regularly. Aim for at least 30 minutes of physical activity on most or all days of the week. Regular exercise can lower triglycerides and boost "good" cholesterol. Try to incorporate more physical activity into your daily tasks — for example, climb the stairs at work or take a walk during breaks.
Avoid sugar and refined carbohydrates. Simple carbohydrates, such as sugar and foods made with white flour or fructose, can increase triglycerides.
Lose weight. If you have mild to moderate hypertriglyceridemia, focus on cutting calories. Extra calories are converted to triglycerides and stored as fat. Reducing your calories will reduce triglycerides.
Choose healthier fats. Trade saturated fat found in meats for healthier fat found in plants, such as olive and canola oils. Instead of red meat, try fish high in omega-3 fatty acids — such as mackerel or salmon. Avoid trans fats or foods with hydrogenated oils or fats.
Limit how much alcohol you drink. Alcohol is high in calories and sugar and has a particularly potent effect on triglycerides. If you have severe hypertriglyceridemia, avoid drinking any alcohol.
What about medication?
If healthy lifestyle changes aren't enough to control high triglycerides, your doctor might recommend:
Statins. These cholesterol-lowering medications may be recommended if you also have poor cholesterol numbers or a history of blocked arteries or diabetes. Examples of statins include atorvastatin calcium (Lipitor) and rosuvastatin calcium (Crestor).
Fibrates. Fibrate medications, such as fenofibrate (TriCor, Fenoglide, others) and gemfibrozil (Lopid), can lower your triglyceride levels. Fibrates aren't used if you have severe kidney or liver disease.
Fish oil. Also known as omega-3 fatty acids, fish oil can help lower your triglycerides. Prescription fish oil preparations, such as Lovaza, contain more-active fatty acids than many nonprescription supplements. Fish oil taken at high levels can interfere with blood clotting, so talk to your doctor before taking any supplements.
Niacin. Niacin, sometimes called nicotinic acid, can lower your triglycerides and low-density lipoprotein (LDL) cholesterol — the "bad" cholesterol. Talk to your doctor before taking over-the-counter niacin because it can interact with other medications and cause significant side effects.
If your doctor prescribes medication to lower your triglycerides, take the medication as prescribed. And remember the significance of the healthy lifestyle changes you've made. Medications can help — but lifestyle matters, too.
Indexed for The Mayo Clinic by Dragonfly Kingdom Library
|Posted on November 29, 2020 at 3:45 PM||comments (0)|
Insulin and GH are counter-regulatory hormones in terms of glucose and lipid metabolism, but act synergistically in protein metabolism. They also mutually regulate the secretion of each other, forming a complex regulatory network.
The balance between insulin and GH is associated with substrate and energy metabolism. In obesity, the hormonal imbalance (high insulin and low GH) promotes further fat accumulation.
Clinical data from various physiological and pathophysiological conditions with insulin and GH changes indicate that the [insulin]:[GH] ratio correlates negatively with energy expenditure and correlates positively with fat accumulation.
The [insulin]:[GH] ratio may serve as a biomarker for monitoring and predicting the development of obesity. Modulation of insulin–GH balance is a promising target for managing obesity.
Disruption of endocrine hormonal balance (i.e., increased levels of insulin, and reduced levels of growth hormone, GH) often occurs in pre‐obesity and obesity. Using distinct intracellular signaling pathways to control cell and body metabolism, GH and insulin also regulate each other’s secretion to maintain overall metabolic homeostasis. Therefore, a comprehensive understanding of insulin and GH balance is essential for understanding endocrine hormonal contributions to energy storage and utilization. In this review we summarize the actions of, and interactions between, insulin and GH at the cellular level, and highlight the association between the insulin/GH ratio and energy metabolism, as well as fat accumulation. Use of the [insulin]:[GH] ratio as a biomarker for predicting the development of obesity is proposed.
|Posted on November 29, 2020 at 3:35 PM||comments (0)|
Obesogenic effects mediated by sex steroid dysregulation
In addition to nutrient-sensing NRs, such as PPARs, NRs for sex steroid hormones also impact adipose tissue development. The hormones help to integrate metabolic functions among major organs that are essential for metabolically intensive activities like reproduction. Knockouts (KOs) of sex steroid pathway components, e.g. FSH receptor (FORKO), aromatase (ArKO), estrogen receptor (ER) (αERKO), and androgen receptor (ARKO), show that sex steroids are required to regulate adipocyte hypertrophy and hyperplasia. Sex steroids also influence the sex-specific remodeling of specific adipose depots (14,15,16,17). Together with peptide hormones such as GH, sex steroids mobilize lipid stores and help to counteract the actions of insulin and cortisol that promote lipid accumulation in adults. In this way, they are antiobesogenic. Antiandrogenic therapies for prostrate cancer produce weight gain, whereas estrogenic hormone replacement therapy protects against many age- and menopause-related changes in adipose depot remodeling (18). Dietary soy phytoestrogens, such as genistein and daidzein, modulate ER signaling and reverse the truncal fat accumulation in postmenopausal women and in ovarectiomized rodent models (19,20).
In contrast to the antiobesogenic effects of estrogen treatment in adults, fetal or neonatal estrogen exposure can lead to obesity later in life. Mice derived from dams maintained on diets with low phytoestrogen content during pregnancy and lactation experienced elevated serum estradiol levels and fetal estrogenization syndrome. Despite a lower than normal birth weight, both males and females developed obesity at puberty when maintained on soy-free chow (21). Interestingly, another study noted a gender-specific adipogenic effect in immature mice fed a low (or within the normal nutritional range) genistein diet. Adipogenic weight gain was only seen in male mice and this effect reversed at the highest pharmacological dose (22). Furthermore, neonatal exposure to the potent synthetic estrogen, diethylstilbesterol (DES), initially led to depressed body weight that was followed by long-term weight gain by adulthood in female mice (23,24). Male mice exposed to DES in the same way did not become obese but rather showed a dose-dependent decrease in overall body weight (25). These disparate results underscore the important and potentially contrasting effects that the same chemical may have, depending on gender. Thus, differences in outcome elicited by treatment with various classes of ER agonists probably reflects the ability of the compounds to activate the ERs as well as their potential for targeting additional cellular signaling pathways and organ target sites.
Obesogens and central integration of energy balance
Drugs and chemicals that target NRs with direct relevance to adipocyte biology are obvious candidates for obesogen action. Another class of targets would be components of the central mechanisms that coordinate the whole-body response to daily nutritional fluctuations. The hypothalamic-pituitary-adrenal axis plays an important role in regulating appetite to prevent hyperphagia and normalize energy homeostasis. Appetite and satiety are regulated by a variety of monoaminoergic, peptidergic, and endocannabinoid signals that are generated in the digestive tract, adipose tissue, and brain. Any of these signals could be potential obesogen targets. Indeed, body weight disruption is observed in various neurological disorders (schizophrenia, bipolar disorder, and depression), and as a result of some pharmaceutical treatments (atypical antipsychotics, tricyclic antidepressants, selective serotonin reuptake inhibitor antidepressants) intended to treat them (26,27,28). For example, patients undergoing olanzapine therapy experience a dose-dependent weight gain of 5–10 kg/yr (27) compared with patients on therapy with typical antipsychotic drugs (29,30). This topic has been recently reviewed elsewhere (2) and, for brevity, will not be considered further here.
Obesogens and programming of metabolic setpoints
The activity of metabolic sensors, sex steroid regulation, or the perception of hunger and satiety are all important potential obesogen targets. Hyperphagia resulting from disruption of hypothalamic appetite centers provides one plausible way to unbalance the energy equation. Hypothalamic output plays an important role in implementing adaptive responses that establish metabolic setpoints and regulate overall metabolic efficiency. Much of the control over these adaptive processes resides in the hypothalamus-pituitary-thyroid axis that determines systemic thyroid hormone output. Thyroid hormone exerts widespread effects on metabolism and sets the basal metabolic rate. Local conversion of T4 (which is inactive on the thyroid hormone receptor) to the receptor agonist T3 by type 2 deiodinase increases thyroid hormone receptor signaling in a tissue-specific manner. Combined with sympathetic adrenergic activity, elevated thyroid hormone receptor signaling regulates expression of a number of respiratory components, including uncoupling protein-1 in brown adipose tissue and muscle that reduces metabolic efficiency and increases energy expenditure (31). An interesting recent report links the ability of the PPARγ agonist rosiglitazone to 1) reduce sympathetic activity to brown adipose tissue and white adipose tissue; 2) down-regulate hypothalamus-pituitary-thyroid signaling by reducing expression of type 2 and type 1 deiodinases; and 3) decrease expression of the proenergy expenditure peptides CRH and cocaine and amphetamine-regulated transcript in the hypothalamus with positive energy balance (32). Depression of circulating T4 levels, localized decreases in peripheral T3 synthesis or reduced input from the sympathetic nervous system would be expected to blunt adaptive responses and promote a propensity for metabolic syndrome and obesity.
Regulation of glucocorticoid hormone levels is another critical component of the hypothalamic-pituitary-adrenal axis that regulates metabolism in peripheral tissues (including fat) and the stress responses. Glucocorticoids play an important role in adipocyte differentiation, and altered glucocorticoid levels can affect long-term metabolic programming and the response to physiological challenges (33,34). Increased glucocorticoid production or inhibited local inactivation via modulation of 11β-hydroxysteroid dehydrogenase type 1 (reactivating) or type 2 (inactivating) enzymes will inappropriately activate the nuclear glucocorticoid receptor, contributing to the development of obesity (35). For example, transgenic overexpression of 11β-hydroxysteroid dehydrogenase (HSD)1 in adipose tissue increases intracellular corticosterone levels, resulting in visceral obesity, glucose intolerance, and insulin resistance. In contrast, targeted overexpression of the inactivating enzyme, 11β-HSD2, protects against diet-induced obesity (36). A number of dietary agents with the ability to elevate or depress glucocorticoid signaling have now been described (37). Notably, the minor component of licorice, glycyrrhetinic acid, or a synthetic derivative carbenoxolone, inhibits 11β-HSD2 activity, raising active glucocorticoid levels (38). Prenatal exposure to carbenoxolone in rats reduces birth weight, raises basal corticosterone, alters hypothalamic expression of GR, and induces hyperglycemia (39,40). Thus, environmental chemicals that can inhibit 11β-HSD2 would be expected to have similar effects (41).
Endocrine Disrupters as Obesogens
The discussion above illustrates several examples of pharmaceutical obesogens that target a variety of cellular pathways to promote adipogenesis and obesity. In light of these observations, it is reasonable to expect that dietary or environmental chemicals that target the same pathways would produce comparable effects. We will point out several classes of potential environmental endocrine-disrupting chemicals that also have the potential to act as obesogens. Cellular targets are indicated where they are known.
Bisphenol A (BPA) and xenoestrogens
Several prominent xenoestrogenic pollutants exhibit obesogenic properties. BPA and nonylphenols are essentially ubiquitous in human populations through their wide use in industrial and consumer products (e.g. leachates from polycarbonate plastics for BPA or alkylphenol polyethoxylate detergents as a source of nonylphenol). BPA is routinely detected in human serum within the range of 0.3–4.4 ng/ml (1.3–19 nm) (42,43), and a positive association has been made between human serum BPA levels and obesity and polycystic ovary syndrome (44). Cell culture studies in the murine 3T3-L1 model demonstrate that such compounds can promote adipogenesis (45,46,47,48). Treatment with BPA in the presence of insulin enhances the differentiation of 3T3-L1 preadipocytes by up-regulating genes required for adipocyte differentiation (46,49). However, it is not clear whether these effects are mediated exclusively by activation of the nuclear ER or through some other mechanism, because different xenoestrogens have varying effects on adipocyte differentiation (49). In addition to its ability to bind to ERs, BPA has been shown to activate the membrane ER at low doses (50) via the insulin-dependent phosphatidylinositol 3-kinase/Akt kinase pathway, enhancing glucose uptake (45,48). Therefore, it is possible that BPA acts in a nongenomic manner to stimulate adipocyte differentiation, and future studies will be required to sort out the mechanism of action. Consistent with the DES results noted above, prenatal and neonatal exposure of rodents to levels of BPA (equivalent to serum concentrations observed in humans) resulted in increased body weight and hyperlipidemia (51,52). Trends toward increased food intake and decreased activity levels were also noted in these experiments, although the results did not reach statistical significance. It will be important to determine the relative contributions of altered developmental metabolic programming, effects on physical activity, and excess caloric intake on obesity in this model. Taken together, these data suggest that xenoestrogens can exert proadipogenic effects through a number of plausible mechanisms and that more detailed analysis of how xenoestrogens affect weight is warranted.
Organotins are a class of persistent organic pollutants that are widely used in polyvinylchloride plastics, as fungicides and pesticides on crops, as slimicides in industrial water systems, as wood preservatives, and as marine antifouling agents. We and others showed that tributyltin (TBT) and triphenyltin (TPT) are highly selective and potent activators of two different types of NRs: the RXRs (RXRα, -β, and -γ) and PPARγ (53,54). PPARγ and RXRs function as obligate heterodimers and, as noted above, act as metabolic sensors that regulate adipocyte number, size, and function. The ability to target both halves of the RXR-PPARγ heterodimer, or of RXR homodimers simultaneously would be predicted to be particularly effective in eliciting obesogenic effects because adipogenic signaling can be mediated by ligand activation of either type of dimer.
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Obesogens, stem cells and the developmental programming of obesity
A. Janesick B. Blumberg
First published: 28 February 2012 https://doi.org/10.1111/j.1365-2605.2012.01247.xCitations: 93
Bruce Blumberg, Department of Developmental and Cell Biology, 2011 BioSci 3, University of California, Irvine, CA 92697‐2300, USA. E‐mail: email@example.com
Obesogens are chemicals that directly or indirectly lead to increased fat accumulation and obesity. Obesogens have the potential to disrupt multiple metabolic signalling pathways in the developing organism that can result in permanent changes in adult physiology. Prenatal or perinatal exposure to obesogenic endocrine disrupting chemicals has been shown to predispose an organism to store more fat from the beginning of its life. For example, excess oestrogen or cortisol exposure in the womb or during early life resulted in an increased susceptibility to obesity and metabolic syndrome later in life. This review focuses on the effects of environmental chemicals, such as the model obesogen, tributyltin (TBT), on the development of obesity. We discuss evidence linking the obesogenic effects of TBT with its ability to activate the peroxisome proliferator‐activated receptor gamma and stimulate adipogenesis. We also discuss how TBT and other environmental obesogens may lead to epigenetic changes that predispose exposed individuals to subsequent weight gain and obesity. This suggests that humans, who have been exposed to obesogenic chemicals during sensitive windows of development, might be pre‐programmed to store increased amounts of fat, resulting in a lifelong struggle to maintain a healthy weight and exacerbating the deleterious effects of poor diet and inadequate exercise.
We are in the midst of a worldwide obesity epidemic that is particularly apparent in the United States. Currently, 34% of American adults are obese (body mass index > 30) and an additional 68% are overweight (BMI > 25), double the worldwide average and 10 times the rates in Korea and Japan (Flegal et al., 2010). The fraction of overweight US adults is predicted to increase to 86% by 2020 (Flegal et al., 2010). BMI is a simple measurement that does not distinguish among increased subcutaneous adiposity, which is generally considered to be the preferred storage depot for excess calories (Ibrahim, 2010), increased visceral adiposity, which is a pathological condition that increases the risk of cardiovascular disease, metabolic syndrome and diabetes (Freedland, 2004) and increased muscularity, which is not a risk factor for metabolic diseases. However, the trend towards higher BMI in the population is largely accompanied by increased visceral adiposity and associated metabolic syndrome disorders (Lustig, 2006).
The most typical explanation given for the increased rate of obesity is that consumption of calorie dense food has increased and that physical activity has decreased, the thermodynamic or ‘calories in‐calories out’ model. Obviously, to gain weight, calories consumed must exceed calories burned; however, the situation is not as simple as balancing one’s caloric checkbook. The biochemical nature of the calories consumed plays a very large role in how and where they are stored, as well as in the regulation of appetite and satiety (Lustig, 2006, 2010). In addition, there are considerable differences in how individuals accrue weight given the same amount of excess calories. Once an individual becomes obese, it is difficult to lose weight and sustain weight loss due to highly efficient homeostatic mechanisms regulating energy balance (Butte et al., 2007; Muhlhausler & Smith, 2009).
The observation that people do not accrue weight equally given the same amount of caloric excess highlights the obvious point that individuals are different. Why is it that some apparently have the ability to eat prodigious quantities of food without becoming obese whereas others do not? Do individual differences result in altered metabolic responses to diet; i.e., do variations in personal metabolic set points contribute to obesity? Two lines of evidence suggest that the prenatal environment has a role in establishing such set point differences. First, babies born to mothers who smoked while pregnant exhibited low birth weight and had an increased risk of obesity and metabolic syndrome later in life (Power & Jefferis, 2002; Oken et al., 2005; Al Mamun et al., 2006). Second, babies who received inadequate nutrition in utero grew up to become adults with higher rates of cardiovascular disease (Barker & Osmond, 1986, 1988; Barker et al., 1989). The Developmental Origins of Health and Disease (DOHaD) model proposes that the prenatal and early life environment plays a key role in establishing life‐long patterns of health and disease (Gluckman & Hanson, 2004). The DOHaD model holds that the development of chronic diseases (or the lack of chronic disease) is influenced by environmental factors (amount and quality of diet, chemical exposure, maternal stress, etc.) acting in early life that interact with genetic differences and factors associated with adult lifestyle. Simplistically, the prenatal environment elicits corresponding changes in the foetus that adjust metabolism to match the projected caloric environment. However, metabolic changes that favour the most effective use of scarce calories will not be adaptive when calories are in excess as in modern societies (Gluckman et al., 2008). There is some evidence to suggest that ‘catch‐up growth’ in early life is a key factor predisposing individuals towards obesity, insulin resistance and cardiovascular disease (Ong et al., 2000; Ong & Dunger, 2002). Thus, while individuals appear outwardly normal, early life events occurring during critical developmental time windows (e.g., perinatally) may lead to permanent changes that are manifested at adulthood (Hanson & Gluckman, 2008). Although the bulk of evidence related to DOHaD comes from nutritional studies, there is no reason to suppose that other factors, such as prenatal stress (Entringer et al., 2008, 2009) and exposure to endocrine disrupting chemicals (EDCs) (Janesick & Blumberg, 2011a), will not elicit similar changes in metabolic programming. Adipogenesis, weight control and metabolism are under hormonal control and are thus susceptible to interference by EDCs. EDC exposure has been linked with diabetes and metabolic syndrome, which may be related to, or independent from their effects on obesity (Lee et al., 2010; Sergeev & Carpenter, 2010, 2011).
‘Obesogens’ are chemical compounds that can promote obesity by increasing the number of fat cells (and fat storage into existing fat cells), by changing the amount of calories burned at rest, by altering energy balance to favour storage of calories and by altering the mechanisms through which the body regulates appetite and satiety. Our environmental obesogen hypothesis proposes that a subset of EDCs could promote the development of obesity. Although initially controversial, the obesogen hypothesis has gained momentum in recent years with the identification of obesogenic chemicals that promote adipogenesis and obesity in animals and humans (Newbold et al., 2009; Janesick & Blumberg, 2011a,b,c; La Merrill & Birnbaum, 2011; Tang‐Peronard et al., 2011). Perhaps most significantly, several classes of pharmaceutical drugs have been linked with weight gain and obesity in humans. Among these are thiazolidinedione anti‐diabetic drugs (Larsen et al., 2003; Rubenstrunk et al., 2007), tricyclic antidepressants (Berken et al., 1984), selective serotonin reuptake inhibitors (Fava, 2000) and atypical anti‐psychotic drugs, such as olanzapine (Nemeroff, 1997). Considering that exposure to these drugs has been linked with obesity in humans, it is reasonable to suppose that exposure to EDCs targeting the same pathways will produce similar outcomes. For example, thiazolidinediones activate the peroxisome proliferator‐activated receptor gamma (PPARγ), a ligand‐dependent transcription factor that is a key regulator of adipogenesis (Evans et al., 2004; Tontonoz & Spiegelman, 2008). Chemicals that activate PPARγ should have the same effect.
Indeed, we and others identified the organotin tributyltin (TBT) as a xenobiotic obesogen (Kanayama et al., 2005; Grun et al., 2006). TBT and the related chemical, triphenyltin (TPT), are nanomolar affinity ligands for PPARγ and its heterodimeric partner, the retinoid X receptor (RXR) that were shown to induce adipogenesis in preadipocyte cell lines, such as 3T3‐L1 cells (Kanayama et al., 2005; Grun et al., 2006). Currently, organotins are prevalent used in industry, as fungicides, wood preservatives and heat stabilizers in polyolefin plastics (Piver, 1973; Nath, 2008). Organotins, including TBT have been documented in house dust, suggesting that exposure from sources other than food may be widespread (Kannan et al., 2010). Although TBT has largely been phased out of agricultural use, TPT remains in use as a fungicide and miticide. Organotins are lipophilic and have been shown to bioaccumulate in bacteria, algae and aquatic invertebrates (Hoch, 2001). Although TBT is most famous for its sex altering effects on gastropod mollusks (Blaber, 1970; Gibbs & Bryan, 1986) and fish (Shimasaki et al., 2003), we unexpectedly found that Xenopus laevis tadpoles exposed to low levels of TBT exhibited ectopic fat cell production (Grun et al., 2006). In mice, prenatal exposure to TBT during gestation resulted in premature accumulation of fat in adipose tissues at birth and increased fat depot size at 10 weeks of age, although, the exposed mice were slightly smaller (Grun et al., 2006). The main conclusion from these studies was that the tendency to store excess fat was programmed before birth due to TBT exposure. Subsequent experiments aimed at understanding the mechanisms underlying the effects of prenatal TBT exposure revealed that a single prenatal treatment with TBT or with the pharmaceutical obesogen, rosiglitazone (ROSI), altered the fate of multipotent mesenchymal stromal stem cells (MSCs). MSCs normally give rise to several tissue types in vivo, including bone, adipose and cartilage (Pittenger et al., 1999). In offspring of pregnant dams treated with a single dose of TBT or ROSI, MSCs derived from white adipose tissue were predisposed to become adipocytes. MSCs derived from obesogen treated animals were about twice as likely to differentiate into adipocytes in culture as control cells and this frequency was further increased by subsequent in vitro treatment with TBT or ROSI (Kirchner et al., 2010). The ability of these cells to differentiate into bone was correspondingly inhibited (Kirchner et al., 2010). The ability of TBT or ROSI to induce adipogenesis in MSCs (Kirchner et al., 2010) or in 3T3‐L1 preadipocytes (Li et al., 2011) was completely dependent on activation of PPARγ, suggesting that the in vivo effects of these compounds similarly depend on PPARγ. However, this remains to be demonstrated.
The topic of obesogens and obesogen action has been extensively reviewed in recent years (Grun & Blumberg, 2009a,b; Grun, 2010; Newbold, 2010, 2011; Blumberg, 2011; Heindel, 2011; Janesick & Blumberg, 2011a,b,c; Tang‐Peronard et al., 2011) as have the effects of EDCs on metabolism (Diamanti‐Kandarakis et al., 2009; Casals‐Casas & Desvergne, 2011). In this review, we highlight likely mechanisms for obesogen action and summarize recent studies linking EDC exposure with obesity in humans.
Obesogens acting on sex steroid receptors
Estrogens in the adult are protective against abdominal obesity and metabolic disease whereas perinatal oestrogen exposure has the opposite effect (see below). Ovariectomized rats (a model for menopause in women) developed abdominal obesity, which was reversed upon treatment with oestrogen (Laudenslager et al., 1980; Wade et al., 1985). Consistent with this observation, loss‐of‐function in the oestrogen receptor alpha (ERα) resulted in increased white adipose depot size, central weight gain and impaired glucose metabolism (Heine et al., 2000; Cooke et al., 2001). Knockout of P450 aromatase in mice inhibited the conversion of testosterone to estradiol, producing obese animals (Jones et al., 2000); loss of the human CYP19A1 (aromatase) gene produced metabolic disease, fatty liver and abdominal obesity (Maffei et al., 2007).
In contrast to its effects in adults, perinatal exposure to excess oestrogen promoted weight gain. Mice treated neonatally with the potent synthetic oestrogen diethylstilbesterol (DES) gave birth to pups that were initially smaller, but became heavier later in life (Newbold et al., 2005, 2008, 2009; Newbold, 2010, 2011). Similarly, treatment of pregnant mouse (Cagampang et al., 2007) or rat (Rubin et al., 2001) dams with the environmental oestrogen bisphenol‐A (BPA) resulted in smaller offspring that exhibited ‘catch‐up’ growth and were significantly heavier as adults. Dichlorodiphenyl‐dichloroethylene (DDE), the major metabolite of the pesticide DDT, is both an oestrogen receptor activator and an anti‐androgen (Kupfer & Bulger, 1976; Kelce et al., 1995). Mothers who lived along the Lake Michigan shoreline where they were exposed to high levels of DDT, were more likely to have a child that exhibited elevated BMI in adulthood (Karmaus et al., 2009). More recently, Mendez and colleagues showed that prenatal exposure to DDE was associated with rapid weight gain in human infants and elevated BMI later in infancy (Mendez et al., 2011). Despite a large number of available studies, the effects of BPA on health remain controversial. Recent human studies have revealed a link between BPA levels and obesity in humans (Carwile & Michels, 2011) and animal studies showed low dose effects of BPA on obesity and diabetes (Rubin, 2011). A recent study tested the effects of prenatal BPA exposure and concluded that while the animals were larger and males had significantly more fat stored at 7 weeks, the animals were neither obese nor did they have increased susceptibility to the effects of high fat diet at adulthood (Ryan et al., 2010). The prevailing view at the moment is that low dose gestational BPA exposure is likely to be causally linked with the development of obesity. Although it appears likely that BPA exerts its obesogenic effects by acting as a developmental oestrogen, the mechanism(s) through which BPA acts to exert its deleterious effects on health need to be more fully elucidated. Ongoing studies in a number of laboratories should shed further light onto this important issue in the near future.
Obesogens and glucocorticoid metabolism
In addition to the sex steroid receptors, disruption of another nuclear hormone receptor regulated signalling pathway, the glucocorticoid receptor, is known to contribute to obesity. Obesity is linked to a general increase of positive feedback within the hypothalamic‐pituitary‐adrenocortical (HPA) axis, leading to an over‐secretion of cortisol from the adrenal gland (Marin et al., 1992; Björntorp, 1993; Chalew et al., 1995; Bjorntorp, 1997; Bjorntorp & Rosmond, 2000). However, rather than causing higher circulating glucocorticoid levels, obesity‐related hypercortisolism is generally peripheral, local and characterized by an impaired ability to clear cortisol in adipose tissue, especially visceral adipose tissue (Rask et al., 2001). Glucocorticoids increased both the differentiation of adipocytes from MSCs and the proliferation of adipocytes. Therefore, excess glucocorticoid levels in adipose depots are likely to stimulate local adipogenesis (Hauner et al., 1989; Bjorntorp, 1991; Bujalska et al., 1999).
One possible mechanism underlying peripheral hypercortisolism is dysregulation of 11β‐hydroxysteroid dehydrogenase type‐1 (11βHSD1), a ubiquitously expressed enzyme that primarily functions to convert inactive glucocorticoids, such as cortisone (humans) and 11‐dehydrocorticosterone (rodents) into their active relatives cortisol and corticosterone (Seckl et al., 2004). Elevated 11βHSD1 has been linked with obesity and metabolic syndrome in humans (Rask et al., 2001; Wake et al., 2003; Valsamakis et al., 2004) and in obese Zucker rats, (Livingstone et al., 2000). Excess glucocorticoid exposure during pregnancy was often associated with lower birth weights, but increased risk of cardiovascular disease, diabetes and hypertension in the adult offspring (Seckl, 2001). Maternal stress has been linked with increased levels of corticotropin‐releasing hormone, increased cortisol secretion and reduced birth weight in the offspring (Weinstock, 2005; Entringer et al., 2009, 2010). Monkeys treated with the synthetic glucocorticoid dexamethasone during pregnancy produced offspring that were normal at birth, but exhibited significant weight gain at 2 months of age, subsequently became obese and developed metabolic syndrome (increased blood pressure, high total cholesterol, decreased HDL and insulin resistance) (Schlumbohm et al., 2007).
Activity of the hypothalamic–pituitary–adrenocortical (HPA) axis that regulates glucocorticoid homeostasis is tightly regulated; therefore, it is possible that any EDC that perturbs the set point of this axis in early life could contribute to subsequent obesity. Such a mechanism could account, as least in part, for why many people cannot lose weight effectively. There are many possible mechanisms through which EDCs could modulate glucocorticoid homeostasis to disrupt energy balance, appetite and the stress response (Odermatt & Gumy, 2008). As 11βHSD1 catalyzes the conversion of inactive to active glucocorticoids, increasing the activity of 11βHSD1 could readily disrupt the HPA axis. This is generally prevented in the foetus because placental 11βHSD2, which catalyzes the conversion of active to inactive glucocorticoids, is highly expressed throughout pregnancy to reduce foetal cortisol exposure (Edwards et al., 1993). Prenatal inhibition of 11βHSD2 by carbenoxolone administration resulted in reduced birth weight, increased anxious behaviour and increased secretion of corticotropin‐releasing hormone in rats (Welberg et al., 2000). Therefore, increased glucocorticoid transport to the foetus by hyperactivating 11βHSD1, or inhbiting 11βHSD2 in the placenta are potential mechanisms through which EDCs might disrupt the HPA axis. Dithiocarbamates decreased 11βHSD2 activity in vitro (Atanasov et al., 2003) as did organotins (Atanasov et al., 2005). Moreover, dibutyltin inhibited the binding of ligands to the glucocorticoid receptor and the ability of this receptor to inhibit cytokine activity and inflammation (Gumy et al., 2008). Another potential mechanism for altered glucocorticoid homeostasis could be alterations in the levels of corticosteroid‐binding globulin (CBG) (Fernandez‐Real et al., 2002). Adipose tissue that is deficient in CBG cannot evacuate excess cortisol to the blood; moreover, CBG deficiency in humans leads to increased proliferation and differentiation of preadipocytes into adipocytes (Joyner et al., 2003). Therefore, exposure to EDCs that decrease CBG activity might also lead to obesity in the adult. Disruption of glucocorticoid action, stress and obesity are fertile areas for future studies because very little research has addressed EDCs and the HPA axis.
Peroxisome proliferator‐activated receptors as obesogen targets
The peroxisome proliferator activated receptors (PPARs) are a family of nuclear hormone receptors that respond to fatty acids and related ligands (Casals‐Casas et al., 2008; Casals‐Casas & Desvergne, 2011). There are three PPARs, PPARα, PPARβ/δ and PPARγ that all form obligate heterodimers with RXR to regulate the expression of target genes at the transcriptional level (Tontonoz & Spiegelman, 2008). PPARγ is considered to be the master regulator of adipogenesis (Evans et al., 2004) and plays key roles in nearly all aspects of adipocyte biology (Tontonoz & Spiegelman, 2008). Thiazolidinediones, which combat type 2 diabetes, are potent activators of PPARγ (Lehmann et al., 1995) and stimulation of PPARγ‐regulated transcription is obesogenic, per se (Janesick & Blumberg, 2011b). Therefore, PPARγ has become a focus of many recent obesity‐related studies. The ligand‐binding pocket of PPARγ is large (Nolte et al., 1998) and can accommodate various chemical structures (Maloney & Waxman, 1999). The mechanistic basis for TBT‐promoted adipogenesis was most strongly supported by evidence that TBT is an agonist for both PPARγ and RXR (Kanayama et al., 2005; Grun et al., 2006). Competitive binding assays showed that TBT has comparable affinity to synthetic RXR agonists for RXR (Grun et al., 2006). The crystal structure of TBT along with the RXRα ligand binding domain, plus a coactivator fragment, showed that TBT binds covalently to RXR (le Maire et al., 2009), which means that it will not readily dissociate once attached. It has been proposed that TBT acts through RXR to promote adipogensis and obesity (le Maire et al., 2009). However, treatment with the potent PPARγ antagonist T0070907 (Lee et al., 2002), inhibited TBT‐ or ROSI‐stimulated adipogenesis in mouse and human MSCs (Kirchner et al., 2010), whereas treatment with the related PPARγ antagonist GW9662 blocked adipogenesis in 3T3‐L1 preadipocytes (Li et al., 2011). The conclusion from these studies was that the stimulation of adipogenesis in MSCs and cell lines by ROSI or TBT required activation of PPARγ.
Because PPARγ is the master regulator of adipogenesis, it is clear that activation of PPARγ by EDCs is a potential risk factor for obesity. However, TBT is not the most common EDC to which humans are exposed. Phthalates are ubiquitous organic chemicals that give plastics, such as polyvinyl chloride (PVC), more flexibility and durability and readily leach into food, from medical devices and materials used in construction and manufacturing. Some phthalates were shown to be PPARγ agonists (Hurst & Waxman, 2003) and stimulated the proliferation of adipocytes in the 3T3‐L1 cell culture model (Feige et al., 2007). Phthalate metabolites were associated with increased waist circumference in men (Stahlhut et al., 2007), and therefore, are predicted to be obesogenic. It is quite likely that other xenobiotic chemicals activate PPARγ and may contribute to the aetiology of obesity (Janesick & Blumberg, 2011b). Screening efforts such as the EPA’s Toxcast (Dix et al., 2007; Knudsen et al., 2011) and the joint NIEHS/EPA/FDA Tox21 (Shukla et al., 2010) are likely sources for the identification of new obesogens that act on PPARγ and other biological targets.
Intriguingly, it has recently been shown that in addition to its known effects in adipocytes and MSCs, PPARγ plays an important role in the brain by controlling appetite and metabolism in response to a high fat diet (Lu et al., 2011; Myers & Burant, 2011; Ryan et al., 2011). Specifically activating PPARγ in the brain lead to increased feeding and accrued body weight whereas blockade of PPARγ or PPARγ loss‐of‐function lead to decreased consumption of high fat, but not normal diet. The conclusion from these studies was that tissue‐specific regulation of PPARγ action may play an important role in the outcome of exposure to chemicals that regulate PPARγ and in the body’s response to dietary excesses. The identification of other PPARγ disruptors, as well as the molecular pathways targeted by EDC‐PPARγ action that reprogram stem cell fate to favour obesity will be important areas for future research.
Epigenetics connects environmental exposures with gene expression
Obesogens are predicted to act prenatally by eliciting epigenetic modifications that alter the expression of key genes in adipogenic pathways. Epigenetic modifications in genes responsible for regulating metabolism, body weight and fat deposition could result in developmental plasticity that allow an organism to make rapid adaptations to changing environments, typically by altering levels of gene expression via DNA methylation or modification of histone proteins (Gluckman & Hanson, 2004; Godfrey et al., 2007, 2011; Gluckman et al., 2008; Hanson & Gluckman, 2008; Hanson et al., 2011). Epigenetic changes that occur during germ cell development can potentially lead to transgenerational effects that may persist for many generations after the initial exposure (Skinner, 2010; Skinner et al., 2011).
Numerous studies have shown that changes in the nutritional environment lead to alterations in the methylation status of genes (Burdge & Lillycrop, 2010a,b; Jackson et al., 2010; Lillycrop & Burdge, 2011; Godfrey et al., 2011; Hochberg et al., 2011; Lillycrop, 2011). Foetal liver derived from rats fed a low‐protein diet showed promoter hypermethylation in the liver X‐receptor (LXR) (van Straten et al., 2010) and hypomethylation of PPARα (Lillycrop et al., 2008). The methylation‐deficient status of PPARα was rescued by supplementing the low‐protein diet with the methyl donor, folic acid (Lillycrop et al., 2008). Increased methylation of the RXRα promoter in humans was associated with increased fat mass at 9 years of age (Godfrey et al., 2011). Considered together, it is reasonable to infer that such epigenetic changes could lead to disturbances in metabolism and lipid homeostasis that might be causally linked to obesity. Further studies will be illuminating in this regard.
If changes in prenatal nutrition can lead to epigenetic changes, does exposure to EDCs elicit the same effects? Consistent with this possibility, chemical‐induced alterations in DNA methylation status were observed for diethylstilbestrol (DES) (Li et al., 1997), TCDD (Wu et al., 2004), vinclozolin (Anway et al., 2005), BPA (Bernal & Jirtle, 2010) and TBT (Kirchner et al., 2010). DNA methyltransferase activity was altered in rat embryos, depending on whether the embryo was exposed to TCDD, DES or polychlorinated biphenyl‐153 (PCB153) (Wu et al., 2006). Thus, although the evidence is still emerging, EDCs can affect the expression levels of DNA and histone methyltransferases that might lead to subsequent broad impacts on gene expression, including genes that are important for metabolism and obesity.
Although the potential for EDCs to alter epigenetic programming to favour altered gene expression definitely exists (Jackson et al., 2010; Lillycrop & Burdge, 2011; Hochberg et al., 2011; Lillycrop, 2011) evidence supporting specific mechanisms of action is scant. One mechanism that has been described concerns epigenetic modifications that alter stem cell fate (Kirchner et al., 2010; Janesick & Blumberg, 2011a). Adipogenesis is a differentiation event in the mesodermal lineage in which MSCs or more lineage‐restricted derivatives give rise to adipocytes. MSCs harvested from epididymal or ovarian fat pads of mice exposed to TBT in utero differentiated into significantly more fat cells, compared with controls, whereas fewer MSCs could differentiate into osteocytes (Kirchner et al., 2010). TBT likely induced epigenetic changes within the MSC compartment that promoted demethylation of adipogenic genes, thereby biasing the MSC compartment to favour the adipocyte lineage (Kirchner et al., 2010). Uninduced MSCs harvested from mice exposed to TBT in utero showed decreased methylation in the gene encoding fatty acid binding protein 4 (FABP4), a marker of adipocytes; suggesting that the MSC population had already been epigenetically modified to favour adipogenesis (Kirchner et al., 2010). Future studies will be needed to identify which regulatory genes have had their expression altered by prenatal exposure to TBT and other obesogens, whether these are the result of epigenetic changes and if the changes elicited persist in future generations.
Conclusions and future prospects
Unhealthy food consumed in excessive amounts and insufficient physical activity are undoubtedly associated with obesity. Whether these are the major and proximate causes of obesity, as is commonly believed, or whether there are other significant causes for obesity remain to be demonstrated. Moreover, it currently remains unknown to what extent obesogen exposure interacts with dietary excesses and lifestyle factors to affect obesity. It is indisputable that following commonly espoused nutritional guidelines (decreased fat consumption, increased carbohydrate consumption) has not resulted in a leaner population. Rather, the opposite is true; we now have an epidemic of obesity in infants (Kim et al., 2006), as well as in children and adults. This suggests that obesity is being programmed prenatally or in early childhood. There is increasing evidence that supports the proposal that environmental endocrine disrupting chemicals (Janesick & Blumberg, 2011a), together with calorie‐dense modern diets (Lustig, 2006) may contribute to the early life programming of obesity. Prenatal exposure to obesogens is likely to be an underestimated contributor to the obesity epidemic; moreover, a variety of persistent organic pollutants have been linked with obesity in human studies (Carwile & Michels, 2011; Lee et al., 2011a,b, 2012; Mendez et al., 2011; Tang‐Peronard et al., 2011). It will be important in the future to determine which of these chemicals are causally linked with adipogenesis and obesity using studies in appropriate animal models. Prenatal exposure to TBT, a chemical for which the mechanism of action is known, predisposed exposed individuals to produce more fat cells (Kirchner et al., 2010) and accrue increased adipose depot mass (Grun et al., 2006). This suggests that the DOHaD model is applicable to the effects of chemical exposure.
There are numerous EDCs (e.g., BPA, brominated flame retardants and phthalates), more prevalent in the environment than TBT that have been linked to metabolic disease (Casals‐Casas et al., 2008; Desvergne et al., 2009; Rubin & Soto, 2009; Vandenberg et al., 2009; Eskenazi et al., 2011; Harley et al., 2011; Rubin, 2011). The metabolic pathways targeted by most of these chemicals remain to be determined; although, some likely pathways are currently under study. The establishment of firm links between EDC exposure and obesity will require elucidation of the underlying mechanisms. Understanding how chemicals enter the body and are transferred to the developing foetus is still not well understood and requires further study. Determining the epigenetic basis of how early life exposure to EDCs modulates the developmental programming of future health and disease will provide answers to the mechanistic questions regarding how obesogens disrupt the endocrine system. There is much yet to learn about how EDC exposures reprogram stem cell fate to favour obesity and diabetes and to what extent these effects can be reduced or eliminated by dietary, behavioural or pharmaceutical interventions.
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