Role of pregnane X receptor in diet-induced obesity and metabolic syndrome

Metabolic syndrome, driven mainly by obesity, has become a global epidemic, increasing the risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). When compared to non-Hispanic whites, diabetes is twice as prevalent in African Americans (AAs) regardless of age and sex. An important observation is that low plasma levels of adiponectin, a protein secreted by adipose tissue, have been implicated in obese AAs in the development of T2D. While a high-fat diet (HFD) is the major cause of obesity and insulin resistance, specific genes that determine cell insulin sensitivity to obesity remain elusive [6-10]. Our recent data uncovered an unexpected role of pregnane X receptor (PXR; NR1I2), a nuclear receptor which defends against potentially toxic foreign chemicals, in predisposing mice to HFD-induced obesity. While HFD-fed wild type (WT) mice gained weight, weight gain was greatly attenuated in HFD-fed PXR-knockout (PXR-KO) mice. Thus, PXR-KO mice were resistant to HFD-induced obesity. Unexpectedly, the PXR-KO mice exhibited impaired induction of glucokinase involved in glucose utilization with elevated fasting glucose levels and impaired glucose tolerance, characteristic of T2D. Furthermore, PXR-KO mice on control diet exhibited hypoadiponectinemia compared with WT mice, suggesting that dysregulated adiponectin signaling may predispose PXR-KO mice to HFD-induced diabetes common among AAs. Based on these findings, we hypothesize that PXR deficiency results in impaired adiponectin signaling leading toinsulin resistance and glucose intolerance with more prominent race and sex differences in AAs. The following specific aims will explore the role of PXR in obesity and metabolic syndrome.