Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat

In response to moderately increased dietary fat content, melanocortin-4 rec eptor-null mutant (MC4R(-/-)) mice exhibit hyperphagia and accelerated weig ht gain compared to wild-type mice. An increased feed efficiency (weight ga in/kcal consumed) argues that mechanisms in addition to hyperphagia are ins trumental in causing weight gain. We report two specific defects in coordin ating energy expenditure with food intake in MC4R(-/-) mice. Wild-type mice respond to an increase in the fat content of the diet by rapidly increasin g diet-induced thermogenesis and by increasing physical activity, neither o f which are observed in MC4R(-/-) mice. Leptin-deficient and MC3R(-/-) mice regulate metabolic rate similarly to wild-type mice in this protocol. Mela nocortinergic pathways involving MC4-R-regulated neurons, which rapidly res pond to signals not requiring changes in leptin, thus seem to be important in regulating metabolic and behavioral responses to dietary fat.