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 homologous recombination, and validated by an acute in vivo study showing a complete lack of effect of the beta 3-adrenoceptor agonist CL 316,243 on the metabolic rate of homozygous null (-/-) mice. In brown adipose tissue, beta 3-adrenoceptor disruption induced a 66% decrease (P < 0.005) in beta(1)-adrenoceptor mRNA level, whereas leptin mRNA remained unchanged, Chronic energy balance studies in chow-fed mice showed that in -/- mice, body fat accumulation was favored (+41%, P < 0.01), with a slight increase in food intake (+6%, NS), These effects were accentuated 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 percentage of body fat in high fat-fed -/- mice suggests that the threshold of body fat content inducing leptin secretion is higher in -/- than in control mice, Taken together, these studies demonstrate that beta(3)-adrenoceptor disruption creates conditions which predispose to the development of obesity.