Targeted disruption of mouse ␤ 3 -adrenoceptor was generated by homologous recombination, and validated by an acute in vivo study showing a complete lack of effect of the ␤ 3 -adrenoceptor agonist CL 316,243 on the metabolic rate of homozygous null ( Ϫ / Ϫ ) mice. In brown adipose tissue, ␤ 3 -adrenoceptor disruption induced a 66% decrease ( P Ͻ 0.005) in ␤ 1 -adrenoceptor mRNA level, whereas leptin mRNA remained unchanged. Chronic energy balance studies in chow-fed mice showed that in Ϫ / Ϫ mice, body fat accumulation was favored ( ϩ 41%, P Ͻ 0.01), with a slight increase in food intake ( ϩ 6%, NS). These effects were accentuated by high fat feeding: Ϫ / Ϫ mice showed increased total body fat ( ϩ 56%, P Ͻ 0.025) and food intake ( ϩ 12%, P Ͻ 0.01), and a decrease in the fat-free dry mass ( Ϫ 10%, P Ͻ 0.05), which reflects a reduction in body protein content. Circulating leptin levels were not different in Ϫ / Ϫ 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 Ϫ / Ϫ mice suggests that the threshold of body fat content inducing leptin secretion is higher in Ϫ / Ϫ than in control mice. Taken together, these studies demonstrate that ␤ 3 -adrenoceptor disruption creates conditions which predispose to the development of obesity. ( J. Clin. Invest. 1997. 100:1098-1106.)

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In rodent brown adipose tissue, the b-adrenergic signaling is believed, by an action on PGC-1a, to control UCP1 expression and mitochondriogenesis. We addressed this hypothesis using b 1 /b 2 /b 3 -adrenoceptor knockout (b-less) brown adipocytes in primary culture. In these cells: (a) proliferation and differentiation into multilocular cells were normal; (b) UCP1 mRNA expression was dramatically decreased (by 93%), whereas PGC-1a and mtTFA mRNA expressions were not; (c) UCP1, PGC-1a and COX IV protein expressions were decreased by 97%, 62% and 22%, respectively. Altogether the data show a dissociation between the control of UCP1, which is mostly b-adrenoceptor-dependent and that of PGC-1a and of mitochondriogenesis which are not.

Knockout of the translation inhibitor 4E-BP1 induces an overexpression of uncoupling protein-1 (UCP1) [Nature Medicine 7 (2001) 1128. A possible inverse control of UCP1 and 4E-BP1 expressions in mouse brown adipose tissue was investigated. Cold-exposure, which increases the expression of UCP1, decreased that of 4E-BP1 mRNA in wild type but not in b 1 =b 2 =b 3 -adrenoceptor knockout mice. Administration of the b 3 -adrenoceptor agonist CL 316 246 decreased 4E-BP1 mRNA by 75% and protein by 41% after 6 and 48 h, respectively. Our data are the first report of a regulation by the b 3 -adrenoceptor of 4E-BP1 expression. They support a role of the latter in adaptive thermogenesis.