Obesogen

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.

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