AJP - Endocrinology and Metabolism, Vol 268, Issue 4 E678-E684, Copyright © 1995 by American Physiological Society

ARTICLES

Metabolic alterations associated with the antidiabetic effect of beta 3-adrenergic receptor agonists in obese mice

C. M. Arbeeny, D. S. Meyers, D. E. Hillyer and K. E. Bergquist
Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.

Treatment of obese (ob/ob) mice with the beta 3-adrenergic receptor (beta 3-AR) agonist BRL-35135 (1 mg.kg body wt-1.day-1 for 20 days) normalized plasma glucose levels and significantly decreased plasma insulin and nonesterified fatty acid levels. The time frame for the hypoglycemic effect, which reached a maximum after 10 days of treatment, paralleled an increase in brown adipose tissue DNA and protein content. The basal level of mRNA for the beta 3-AR and mitochondrial uncoupling protein was found to be markedly decreased in the ob/ob animals relative to the lean group. Chronic treatment of ob/ob mice for 20 days resulted in a twofold increase in beta 3-AR mRNA and a fivefold increase in uncoupling protein mRNA in brown adipose tissue relative to the placebo group. These findings indicate that chronic treatment of ob/ob animals with a beta 3-AR agonist results in proliferation of brown adipose tissue, with an upregulation of the beta 3-AR, which is associated with a decrease in plasma glucose, insulin, and nonesterified fatty acid levels.

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