Lack of Responses to a beta(3)-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice

Stimulation of beta (3)-adrenergic receptors increases metabolic rate via l ipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose t issue (BAT), Other acute effects include decreased gastrointestinal motilit y and food intake and increased insulin secretion. Chronic treatment with a beta (3) agonist ameliorates diabetes and obesity in rodents. We studied t he effects of beta (3) stimulation in A-ZIP/F-1 mice, which have virtually no WAT, a reduced amount of BAT, severe insulin resistance, and diabetes. I n contrast with wild-type mice, treatment of A-ZIP/F-1 mice with CL316243, a beta (3)-adrenergic agonist, did not increase O-2 consumption. A single d ose of CL316243 produced a 2-fold increase in serum free fatty acids, a 53- fold increase in insulin, and a 2.4-fold decrease in glucose levels in wild -type mice but no change in A-ZIP/F-1 animals. The A-ZIP/F-1 mice also did not show reduced gastrointestinal motility or 24-h food intake during beta (3) stimulation. Chronic administration of CL316243 to the A-ZIP/F-1 mice d id not improve their thermogenesis, hyperglycemia, or hyperinsulinemia, Thu s, all of the beta (3) effects studied were absent in the lipoatrophic A-ZI P/F-1 mice, including the effects on nonadipose tissues. From these results , we suggest that all of the effects of beta (3) agonists are initiated at the adipocyte with the nonadipose effects being secondary events presumably mediated by signals from adipose tissue.