Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway

Leptin deficiency results in a complex obesity phenotype comprising both hy perphagia and lowered metabolism. The hyperphagia results, at least in part , from the absence of induction by leptin of melanocyte stimulating hormone (MSH) secretion in the hypothalamus; the WISH normally then binds to melan ocortin-4 receptor expressing neurons and inhibits food intake. The basis f or the reduced metabolic rate has been unknown. Here we show that leptin ad ministered to leptin-deficient (ob/ob) mice results in a large increase in peripheral MSH levels; further, peripheral administration of an MSH analogu e results in a reversal of their abnormally low metabolic rate, in an accel eration of weight loss during a fast, in partial restoration of thermoregul ation in a cold challenge, and in inducing serum free fatty acid levels. Th ese results support an important peripheral role for WISH in the integratio n of metabolism with appetite in response to perceived fat stoves indicated by leptin levels.