METABOLIC ALTERATIONS ASSOCIATED WITH THE ANTIDIABETIC EFFECT OF BETA(3)-ADRENERGIC RECEPTOR AGONISTS IN OBESE MICE

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.