PXR ablation alleviates diet-induced and genetic obesity and insulin resistance in mice. Diabetes 2013

The pregnane X receptor (PXR), along with its sister receptor constitutive androstane receptor (CAR), was initially character-ized as a xenobiotic receptor that regulates drug metabolism. In this study, we have uncovered an unexpected endobiotic role of PXR in obesity and type 2 diabetes. PXR ablation inhibited high-fat diet (HFD)–induced obesity, hepatic steatosis, and insulin resistance, which were accounted for by increased oxygen con-sumption, increased mitochondrial b-oxidation, inhibition of hepatic lipogenesis and inflammation, and sensitization of insulin signaling. In an independent model, introducing the PXR2/2 allele into the ob/ob background also improved body composition and relieved the diabetic phenotype. The ob/ob mice deficient of PXR showed increased oxygen consumption and energy expenditure, as well as inhibition of gluconeogenesis and increased rate of glucose disposal during euglycemic clamp. Mechanistically, th