Mutation of the RIIbeta subunit of protein kinase A prevents diet-induced insulin resistance and dyslipidemia in mice.
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 RIIbeta 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. RIIbeta(-/-) 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 RIIbeta(-/-) mice compared with wild-type mice. Taken together, these data demonstrate that loss of RIIbeta protects mice from diet-induced obesity, insulin resistance, and dyslipidemia.
Schreyer
S A
SA
Department of Pathobiology, University of Washington, Seattle, Washington 98195, USA.
Cummings
D E
DE
McKnight
G S
GS
LeBoeuf
R C
RC
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001835:Body Weight; D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics*; D003920:Diabetes Mellitus / Q000209:etiology / Q000235:genetics; D004032:Diet / Q000009:adverse effects*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006949:Hyperlipidemias / Q000209:etiology* / Q000517:prevention & control*; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D010641:Phenotype; D012016:Reference Values
D054757:Cyclic AMP-Dependent Protein Kinase RIIbeta Subunit; D007328:Insulin; D008055:Lipids; C517838:Prkar2b protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose