ACTIVATION OF BETA(3) ADRENERGIC-RECEPTORS SUPPRESSES LEPTIN EXPRESSION AND MEDIATES A LEPTIN-INDEPENDENT INHIBITION OF FOOD-INTAKE IN MICE

To examine potential interactions between leptin and the beta(3) adren ergic system in the regulation of food intake, we determined the effec ts of treatment with a selective beta(3) adrenergic receptor (AR) agon ist (CL 316,243 [1 mg/kg]) on body weight, food intake, and leptin exp ression. Studies were carried out in C57Bl/6J and FVB male control mic e as well as in mice with targeted disruption of the beta(3) AR gene. These findings were correlated with measurement of the expression in h ypothalamus of neuropeptide Y (NPY) and melanin concentrating hormone (MCH), two neuropeptides that may be involved in the central regulatio n of food intake. Treatment with CL 316,243 (1 mg/kg) for 12 or 24 h d ecreased leptin mRNA abundance and circulating levels to 20% of baseli ne in normal animals. No effect of the CL 316,243 compound was seen in mice with targeted disruption of the beta(3) AR gene. Despite the fal ling leptin levels, beta(3) agonist administration acutely suppressed food intake. Finally, the induced suppression of food intake and lepti n levels occurred despite unchanged or increased hypothalamic expressi on of the orexigenic neuropeptides NPY and MCH. Thus, beta(3) AR agoni sts via beta(3) ARs suppress leptin levels acutely and simultaneously suppress food intake via a mechanism that operates downstream of lepti n and two of its putative central targets.