Activation of β₃ Adrenergic Receptors Suppresses Leptin Expression and Mediates a Leptin-Independent Inhibition of Food Intake in Mice

To examine potential interactions between leptin and the β₃ adrenergic system in the regulation of food intake, we determined the effects of treatment with a selective β₃ adrenergic receptor (AR) agonist (CL 316,243 [1 mgfleg]) on body weight, food intake, and leptin expression. Studies were carried out in C57B1/6J and FVB male control mice as well as in mice with targeted disruption of the β₃ AR gene. These findings were correlated with measurement of the expression in hypothalamus of neuropeptide Y (NPY) and melanin concentrating hormone (MCH), two neuropeptides that may be involved in the central regulation of food intake. Treatment with CL 316,243 (1 mg/kg) for 12 or 24 h decreased leptin mRNA abundance and circulating levels to 20% of baseline in normal animals. No effect of the CL 316,243 compound was seen in mice with targeted disruption of the β₃ AR gene. Despite the falling leptin levels, β₃ agonist administration acutely suppressed food intake. Finally, the induced suppression of food intake and leptin levels occurred despite unchanged or increased hypothalamic expression of the orexigenic neuropeptides NPY and MCH. Thus, β₃ AR agonists via β₃ ARs suppress leptin levels acutely and simultaneously suppress food intake via a mechanism that operates downstream of leptin and two of its putative central targets.