Mutation of the RII beta subunit of protein kinase A prevents diet-inducedinsulin resistance and dyslipidemia in mice

The mechanisms by which obesity contributes to diabetic phenotypes remain u nclear. We evaluated the role of protein kinase A (PKA) signaling events in mediating diabetes associated with obesity. PKA comprises two regulatory s ubunits and two catalytic subunits and is activated by cAMP. The RII beta r egulatory subunit is abundantly expressed in adipose tissue and brain. Knoc kout mice lacking this subunit are lean and display remarkable resistance t o diet-induced obesity. We investigated whether these mice were also resist ant to diet-induced diabetes and whether this effect was dependent on reduc ed adiposity. Mice were fed a high-fat, high-carbohydrate diet and weight g ain and diabetes phenotypes were examined. RII beta (-/-) mice displayed de creased body weights, reduced insulin levels, improved insulin sensitivity, and improved total-body glucose disposal as compared with wild-type contro ls. Plasma levels of VLDL and LDL cholesterol were also reduced in high fat -fed RII beta (-/-) mice compared with wild-type mice. Taken together, thes e data demonstrate that loss of RII beta protects mice from diet-induced ob esity, insulin resistance, and dyslipidemia.