TARGETED GENE DISRUPTION REVEALS A LEPTIN-INDEPENDENT ROLE FOR THE MOUSE BETA(3)-ADRENOCEPTOR IN THE REGULATION OF BODY-COMPOSITION

Targeted disruption of mouse beta(3)-adrenoceptor was generated by hom ologous recombination, and validated by an acute in vivo study showing a complete lack of effect of the beta 3-adrenoceptor agonist CL 316,2 43 on the metabolic rate of homozygous null (-/-) mice. In brown adipo se tissue, beta 3-adrenoceptor disruption induced a 66% decrease (P < 0.005) in beta(1)-adrenoceptor mRNA level, whereas leptin mRNA remaine d unchanged, Chronic energy balance studies in chow-fed mice showed th at in -/- mice, body fat accumulation was favored (+41%, P < 0.01), wi th a slight increase in food intake (+6%, NS), These effects were acce ntuated by high fat feeding: -/- mice showed increased total body fat (+56%, P < 0.025) and food intake (+12%, P < 0.01), and a decrease in the fat-free dry mass (-10%, P < 0.05), which reflects a reduction in body protein content, Circulating leptin levels were not different in -/- and control mice regardless of diet, The significant shift to the right in the positive correlation between circulating leptin and perce ntage of body fat in high fat-fed -/- mice suggests that the threshold of body fat content inducing leptin secretion is higher in -/- than i n control mice, Taken together, these studies demonstrate that beta(3) -adrenoceptor disruption creates conditions which predispose to the de velopment of obesity.