Diazoxide restores beta3-adrenergic receptor function in diet-induced obesity and diabetes.
We previously demonstrated that the expression and function of the adipocyte-specific beta3-adrenergic receptor (beta3AR) are significantly depressed in single gene and diet-induced rodent models of obesity. Furthermore, these models are relatively unresponsive to the anti-obesity effects of beta3AR agonists. Because all of these models are hyperinsulinemic, we hypothesized that hyperinsulinemia could be responsible for this abnormality in beta3AR 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 beta3AR 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-di carboxylate (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 3pAR 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.
Surwit
R S
RS
Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710, USA.
Dixon
T M
TM
Petro
A E
AE
Daniel
K W
KW
Collins
S
S
D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000187:drug effects; D003920:Diabetes Mellitus / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D003981:Diazoxide / Q000494:pharmacology*; D004032:Diet / Q000009:adverse effects*; D002149:Energy Intake; D005947:Glucose / Q000378:metabolism / Q000502:physiology; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D013577:Syndrome
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D008055:Lipids; D011943:Receptors, Adrenergic, beta; D005947:Glucose; D003981:Diazoxide