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