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Diazoxide Restores ß₃-Adrenergic Receptor Function in Diet-Induced Obesity and Diabetes

Departments of Psychiatry and Behavioral Sciences, and Pharmacology (T.M.D., S.C.), Duke University Medical Center, Durham, North Carolina 27710

Address all correspondence and requests for reprints to: Richard S. Surwit, Ph.D., Duke University Medical Center, Box 3842, Durham, North Carolina 27710.

We previously demonstrated that the expression and function of the adipocyte-specific ß₃-adrenergic receptor (ß₃AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the antiobesity effects of ß₃AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in ß₃AR function. The goal of this study was to determine whether lowering insulin with the K-ATP channel agonist, diazoxide (Dz) would reverse the depressed expression and function of the ß₃AR found in a model of diet-induced diabetes and obesity in C57BL/6J (B6) mice. B6 male mice were placed 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-([2-(3-chlorophenyl)-2-hydroxyethyl]-amino]propyl-1,3-benzodioxole-2,2-dicarboxylate (CL; 0.001%, wt/wt), Dz (0.32%, wt/wt), or their combination (CLDz). Dz animals exhibited significantly reduced plasma insulin levels as well as increased ß₃AR expression and agonist-stimulated adenylyl cyclase activity in adipocytes. CLDz was more effective in reducing percent body fat, lowering nonesterified fatty acids, improving glucose tolerance, and reducing feed efficiency than either treatment alone.

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