Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.
There are many different proposed mechanisms through which obesogens can interfere with the body's adipose tissue biology. These mechanisms include alterations in the action of metabolic sensors; dysregulation of sex steroid synthesis, action or breakdown; changes in the central integration of energy balance including the regulation of appetite and satiety; and reprogramming of metabolic setpoints. Some of these proposed pathways include inappropriate modulation of nuclear receptor function which therefore allows the compounds to be classified as endocrine disrupting chemicals that act to mimic hormones in the body, altering the normal homeostasis maintained by the endocrine system.
Obesogens have been detected in the body both as a result of intentional administration of obesogenic chemicals in the form of pharmaceutical drugs such as diethylstilbestrol, selective serotonin reuptake inhibitors, and thiazolidinedione and as a result of unintentional exposure to environmental obesogens such as tributyltin, bisphenol A, diethylhexylphthalate, and perfluorooctanoate.
The term obesogen was coined in 2006 by Felix Grün and Bruce Blumberg of the University of California, Irvine.
Mechanisms of action
There are many ways in which obesogenic drugs and chemicals can disrupt the body's adipose tissue biology. The three main mechanisms of action include alterations in the action of metabolic sensors in which obesogens mimic metabolic ligands acting to either block or upregulate hormone receptors dysregulation of sex steroid synthesis, in which they alter the ratio of sex hormones leading to changes in their control of lipid balance changes in the central integration of energy balance including the regulation of appetite and satiety in the brain and the reprogramming of metabolic setpoints.
Metabolic sensors
Obesogenic drugs and chemicals have been shown to target transcription regulators found in gene networks that function to control intracellular lipid homeostasis and proliferation and differentiation on adipocytes. The major group of regulators that is targeted is a group of nuclear hormone receptors known as peroxisome proliferator activated receptors (PPARα, δ, and γ). These hormone receptors sense a variety of metabolic ligands including lipophilic hormones, dietary fatty acids and their metabolites, and, depending on the varying levels of these ligands, control transcription of genes involved in balancing the changes in lipid balance in the body. To become active and properly function as metabolic sensors and transcription regulators, the PPAR receptors must heterodimerize with another receptor known as the 9-cis retinoic acid receptor (RXR). The RXR receptor itself is the second major target of obesogens next to the PPAR receptors.
The PPARα receptor, when complexed with RXR and activated by the binding of a lipid, promotes peroxisome proliferation leading to increased fatty acid β-oxidation. Substances, such a xenobiotics that target and act as agonists of PPARα, typically act to reduce overall serum concentrations of lipids. In contrast, the PPARγ receptor, when complexed with RXR and activated by the binding of fatty acids or their derivatives, promotes lipid biosynthesis and storage of lipids is favored over fatty acid oxidation. In addition, activation promotes differentiation of preadipocytes and the conversion of mesenchymal progenitor cells to preadipocytes in adipose tissues. Substances that target and act as agonists of PPARγ/RXR complex typically act to increase overall serum concentrations of lipids.
Obesogens that target the PPARγ/RXR complex mimic the metabolic ligands and activate the receptor leading to upregulation of lipid accumulation which explains their obesogenic effects. However, in the case of obesogens that target the PPARα/RXR complex, which when stimulated reduces adipose mass and body weight, there are a few explanations as to how they promote obesity.
The ligand binding pockets of PPARs are very large and unspecified, allowing for different isoforms of the receptor (PPARα, δ, and γ) to be activated by the same agonist ligands or their metabolites. In addition, fatty acid oxidation stimulated by PPARα requires continuous stimulation while only a single activation event of PPARγ is required to permanently increase adipocyte differentiation and number. Therefore, it may be the case that metabolites of PPARα targeting obesogens are also activating PPARγ, providing the single activation event needed to potentially lead to a pro-adipogenic response.
A second explanation points to specific PPARα targeters that have been shown to additionally cause abnormal transcriptional regulation of testicular steroidogenesis when introduced during fetal development. This abnormal regulation leads to a decreased level of androgen in the body which, itself, is obesogenic.
Finally, if PPARα activation occurs during critical periods of development, the resulting decrease in lipid concentration in the developing fetus is recognized by the fetal brain as undernourishment. In this case, the developing brain makes what will become permanent changes to the body's metabolic control, leading to long-term upregulation of lipid storage and maintenance.
Sex steroid dysregulation
Sex steroids normally play a significant role in lipid balance in the body. Aided by other peptide hormones such as growth hormone, they act against the lipid accumulation mediated by insulin and cortisol by mobilizing lipid stores that are present. Exposure to obesogens often leads to a deficiency or change in the ratio between androgen and estrogen sex steroid levels, which modifies this method of lipid balance resulting in lowered growth hormone secretion, hypocortisolemia (low levels of circulating cortisol), and increased resistance to insulin effects.
This alteration in sex steroid levels due to obesogens can vary enormously according to both the sex of the exposed individual as well as the timing of the exposure. If the chemicals are introduced at critical windows of development, the vulnerability of an individual to their effects is much higher than if exposure occurs later in adulthood. It has been shown that obesogenic effects are apparent in female mice exposed to both phytoestrogens and DES during their neonatal periods of development, as they, though born with a lower birth weight, almost always developed obesity, high leptin levels, and altered glucose response pathways. Both phytoestrogen and DES exposed male mice did not develop obesity and, rather, showed decreased body weights with increased exposure confirming the role of gender differences in exposure response. Further studies have shown positive correlations for serum BPA levels with obese females in the human population, along with other xenoestrogen compounds suggesting the parallel roles that these effects may be having on humans.
Central balance of energy
While hormone receptors tend to be the most obvious candidates for targets of obesogens, central mechanisms that balance and regulate the body's nutritional changes on a day-to-day basis as a whole cannot be overlooked. The HPA axis (hypothalamic-pituitary-adrenal) is involved in controlling appetite and energy homeostasis circuits which are mediated by a large number of monoaminoergic, peptidergic (use of hormones as neurotransmitters), and endocannabinoid signals that come from the digestive tract, adipose tissues, and from within the brain. It is these types of signals that provide a likely target for obesogens that have shown to have weight altering effects.
Neuroendocrine effects
Neurological disorders may enhance the susceptibility to develop the metabolic syndrome that includes obesity. Many neuropharmaceuticals used to alter behavioral pathways in patients with neurological disorders have shown to have metabolic altering side-effects leading to obesogenic phenotypes as well. These findings give evidence to conclude that an increase in lipid accumulation can result from the targeting of neurotransmitter receptors by foreign chemicals.See also: #Central integration of energy balance
Peptidergic hormones
Several peptidergic hormone pathways controlling appetite and energy balance —such as those involving ghrelin, neuropeptide Y, and agouti-related peptide — are particularly sensitive to changes in nuclear receptor signaling pathways and can therefore be easily altered by the introduction of endocrine disruptors. Such an alteration can lead to induced feelings of hunger and decreased feelings of fullness causing an increase in food intake and inability to feel satisfied, both characteristic of obesity.
Some xenoestrogens such as BPA, nonylphenol, and DEHP have all shown to act is this way, altering NPY expression and significantly shifting the feeding behaviors of exposed mice. In addition, organotins such as trimethyltin (TMT), triethyltin (TET), and tributyltin (TBT) compounds can exert their effects through similar pathways. TBT can locally disrupt aromatase regulation in the hypothalamus causing the responses of the HPA axis to hormones to become abnormal. TMT works in a similar but unique way, inducing NPY and NPY2 receptor expression initially which later is counteracted by neuronal degeneration in lesions causing decrease in signaling ability.
While an increase in food intake is often the case after exposure, weight gain involves the body's maintenance of its metabolic setpoint as well. Given this information, it is particularly important to note that exposure during development and initial programming of these setpoints can be extremely significant throughout the remainder of life.
Endocannabinoid signaling
A wide range of environmental organotins that mimic petidergic hormones in the HPA axis as mentioned before, additionally mimic lipid activators of the cannabinoid system and inhibit AMPK activity. Endocannaboid levels are high in those suffering from obesity due to hyperactivity of cannaboid signalling pathways. It is these high levels that have been found to be closely associated with increased fat stores linking the lipid activator mimics to the actual disease.
Programming of metabolic set points
Regions in the hypothalamus control the responses that establish an individual's metabolic setpoint and metabolic efficiency. These responses are adaptive in that they vary according to the individual's needs, always working to restore the metabolic setpoint through the increase or decrease of metabolic functions depending on varying energy needs. Since it is adapted, it is expected that it would be able to achieve equilibrium if the lipid balance was altered by hormones via the mechanisms mentioned above. However, since obesogenic phenotypes persist, it can be concluded that adaptive response components of the hypothalamus may be a target of obesogens as well.
Body composition is very much predetermined before birth and changes rarely occur in adulthood. Adipocyte numbers increase during development and come to a plateau, after which adipocytes are restricted to mostly hypertrophic growth and don't seem to change much in cell number. This is demonstrated by the difficulty in altering somatotypes or more simply by the difficulty that goes along with trying to lose weight past a certain point.