|Posted on November 29, 2020 at 3:35 PM|
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.