Lack of Responses to a β3-adrenergic agonist in lipoatrophic A-ZIP/F-1 mice

Stimulation of beta (3)-adrenergic receptors increases metabolic rate via lipolysis in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT), Other acute effects include decreased gastrointestinal motility and food intake and increased insulin secretion. Chronic treatment with a beta (3) agonist ameliorates diabetes and obesity in rodents. We studied the 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. In 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 dose 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 did not improve their thermogenesis, hyperglycemia, or hyperinsulinemia, Thus, all of the beta (3) effects studied were absent in the lipoatrophic A-ZIP/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.