抄録
Obesity and metabolic syndrome diseases have exploded into an epidemic of global proportions. Consumption of calorie-dense food and diminished physical activity are accepted as causal factors for obesity. But could environmental factors expose preexisting genetic differences or exacerbate the root causes of diet and exercise? The “obesogen hypothesis” proposes that environmental chemicals may perturb lipid homeostasis, adipocyte development, or adipose tissue function. Exposure during sensitive developmental windows could result in permanent metabolic changes that increase fat storage. We identified organotins as a novel class of obesogens and showed that the nuclear receptors, RXR and PPARγ are high-affinity molecular targets of tributyltin (TBT). RXR-PPARγ signaling is a key component in adipogenesis and the function of adipocytes. Thus, inappropriate activation of RXR-PPARγ has the potential to strike at the heart of adipose tissue homeostasis. Our results show that TBT promotes adipocyte differentiation, modulates adipogenic genes in vivo, and increases adiposity in mice after in utero exposure. These results are consistent with the environmental obesogen model and suggest that organotin exposure is a previously unappreciated risk factor for the development of obesity and related disorders.
