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Do Environmental Chemicals Make Us Fat?

Obesity is a global pandemic. Nearly 40% of adults and 20% of all children in the United States are classified as obese. There are differences among men and women, race and ethnicity, and regions of the country (1), illustrating in part the complexity of this issue. Because of the relationship between obesity and comorbidities of diabetes, cardiovascular disease, and hypertension—and the attendant human and economic costs (2)—both a cause and a cure have been urgently sought and hotly debated (3). But it is as dangerous as it is seductive to frame the question in terms of a single cause (as the title is framed) because it suggests that a single factor is “causing” the obesity pandemic and, by extension, eliminating this factor will eliminate the problem. It is clearly not that simple. Body weight regulation is highly complex and controlled by a variety of hormones, including hormones regulating glucose homeostasis, hunger and satiety, metabolism, energy balance, and adiposity. Such a complex system could be perturbed by many factors, including nutrition, exercise, sleep cycles, genetics (3), and environmental chemicals (4, 5) acting singly and in concert. So a better question might be, “Do environmental chemicals contribute to the obesity epidemic and, if they do, how do they interact with the other regulators of body weight and what is their contribution?” The article by Shoucri et al. (6) in this issue of Endocrinology adds an important contribution to understanding both the mechanism by which adipocyte development occurs and the importance of environmental chemicals in the obesity epidemic. This article builds on a series of seminal observations about the ability of an environmental chemical—tributyltin (TBT)—to cause increased body weight and fat in mice and for this effect to be passed on to future generations that had not been exposed (transgenerational inheritance) (7). Previously, without a basic mechanistic understanding for this effect, many scientists have dismissed these and other findings, concluding that environmental chemicals do not contribute to the obesity epidemic. Shoucri et al. (6) make several experimental observations relating to the mechanismbywhichTBTcan cause an increase in adiposity during development that should shake us from complacency about the role of environmental chemicals in the obesity epidemic. They showed that an environmental chemical, TBT, can alter the epigenome of mesenchymal stem cells, leading to both a commitment to and differentiation into adipocytes, which in vivo would result in increased numbers of adipose cells and thus to weight gain. Shoucri et al. (6) show convincingly that TBT causes mesenchymal stem cells to commit to the adipocyte lineage in a retinoid X receptor (RXR)–dependent, peroxisome proliferator-activated receptor g (PPAR-g)– independent manner. To do this, they first developed a unique “adipocyte commitment assay” that can distinguish between commitment to becoming an adipocyte and actual differentiation into an adipocyte. They used this assay to show that TBT, or the RXR selective agonist IRX4204, induces mesenchymal stem cells to commit to the adipocyte lineage, whereas the PPAR-g ligand rosiglitazone did not induce commitment but stimulated differentiation. This is strong evidence that signaling through RXR is responsible for adipocyte commitment. Interestingly, TBT can bind to both PPAR-g and to RXR, so this chemical appears to induce both commitment and differentiation in low nanomolar concentrations. Using a combination of RNA sequencing and chromatin immunoprecipitation sequencing, Shoucri et al. (6) also provide important evidence supporting a mechanism