Diazoxide restores beta(3)-adrenergic receptor function in diet-induced obesity and diabetes

We previously demonstrated that the expression and function of the adipocyt e-specific beta(3)-adrenergic receptor (beta(3)AR) are significantly depres sed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the antiobesity effects of beta (3)AR agonists. Because all of these models are hyperinsulinemic, we hypoth esized that hyperinsulinemia could be responsible for this abnormality in b eta(3)AR function. The goal of this study was to determine whether lowering insulin with the K-ATP channel agonist, diazoxide (Dz) would reverse the d epressed expression and function of the beta(3)AR found in a model of diet- induced diabetes and obesity in C57BL/6J (B6) mice. B6 male mice were place d on either high fat (HF) or low fat experimental diets. After 4 weeks, HF- fed mice were assigned to a group: HF or HF containing disodium(R,R)-5- [2- (12-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl-1,3-benzodioxole-2,2-dica rboxylate (CL; 0.001%, wt/wt), Dz (0.32%, wt/wt), or their combination (CLD z). Dz animals exhibited significantly reduced plasma insulin levels as wel l as increased beta(3)AR expression and agonist-stimulated adenylyl cyclase activity in adipocytes. CLDz was more effective in reducing percent body f at, lowering nonesterified fatty acids, improving glucose tolerance, and re ducing feed efficiency than either treatment alone.