Diazoxide Restores β3-Adrenergic Receptor Function in Diet-Induced Obesity and Diabetes

• Published in: Endocrinology (Philadelphia) 2000-10, Vol.141 (10), p.3630-3637
• Main Authors: Surwit, Richard S, Dixon, Tonya M, Petro, Ann E, Daniel, Kiefer W, Collins, Sheila
• Format: Article
• Language: English
• Subjects: Adenylate cyclase; Adipocytes; Adrenergic receptors; Agonists; Animal models; Body fat; Diabetes; Diabetes mellitus; Diet; Feed conversion; Feed efficiency; Glucose tolerance; High fat diet; Hyperinsulinemia; Insulin; Low fat diet; Nutrient deficiency; Obesity; Receptors (physiology)
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/endo.141.10.7726

We previously demonstrated that the expression and function of the adipocyte-specific β3-adrenergic receptor (β3AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the antiobesity effects ofβ 3AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in β3AR 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 β3AR 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 β3AR 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.