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© 2001 by the American Diabetes Association, Inc.
Mutation of the RIIß Subunit of Protein Kinase A Prevents Diet-Induced Insulin Resistance and Dyslipidemia in Mice
1 Department of Pathobiology, University of Washington, Seattle, Washington
2 Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, Washington
3 Department of Pharmacology, University of Washington, Seattle, Washington
The mechanisms by which obesity contributes to diabetic phenotypes remain unclear. We evaluated the role of protein kinase A (PKA) signaling events in mediating diabetes associated with obesity. PKA comprises two regulatory subunits and two catalytic subunits and is activated by cAMP. The RIIß regulatory subunit is abundantly expressed in adipose tissue and brain. Knockout mice lacking this subunit are lean and display remarkable resistance to diet-induced obesity. We investigated whether these mice were also resistant to diet-induced diabetes and whether this effect was dependent on reduced adiposity. Mice were fed a high-fat, high-carbohydrate diet and weight gain and diabetes phenotypes were examined. RIIß-/- mice displayed decreased body weights, reduced insulin levels, improved insulin sensitivity, and improved total-body glucose disposal as compared with wild-type controls. Plasma levels of VLDL and LDL cholesterol were also reduced in high fat–fed RIIß-/- mice compared with wild-type mice. Taken together, these data demonstrate that loss of RIIß protects mice from diet-induced obesity, insulin resistance, and dyslipidemia.
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