THE ROLE OF CONSTITUTIVE ANDROSTANE RECEPTOR AND ESTROGEN SULFOTRANSFERASE IN ENERGY HOMEOSTASIS

Abstract

Obesity and type 2 diabetes are related metabolic disorders of high prevalence. The constitutive androstane receptor (CAR) was initially characterized as a xenobiotic receptor regulating the responses of mammals to xenotoxicants. In this study, I have uncovered an unexpected role of CAR in preventing obesity and alleviating type 2 diabetes. Activation of CAR prevented obesity and improved insulin sensitivity in both the HFD-induced type 2 diabetic model and the ob/ob mice. In contrast, CAR null mice maintained on a chow diet showed spontaneous insulin insensitivity. The metabolic benefits of CAR activation may have resulted from inhibition of hepatic lipogenesis and gluconeogenesis. The molecular mechanism through which CAR activation suppressed hepatic gluconeogenesis might be mediated via peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). CAR can interact with PGC-1α and sequestrate it into promyelocytic leukemia (PML) nuclear bodies, thus preventing the PGC-1α from binding to the promoter region of gluconeogenesis genes. Estrogen sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of estrogens, plays an important role in estrogen homeostasis. Here, I showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone- and high-fat diet-induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased estrogen deprivation and increased estrogenic activity in the liver. Interestingly, the effect of Est was gender specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet β cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of β cell mass in obe males was associated with increased macrophage infiltration and inflammation in white adipose tissue. In summary, I had uncovered critical roles of CAR and EST in energy metabolism and the pathogenesis of type 2 diabetes. Both of CAR and EST may represent novel therapeutic targets in the management type 2 diabetes