Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat
Andrew A. Butler1, Daniel L. Marks2, Wei Fan1, Cynthia M. Kuhn3, Maria Bartolome3
& Roger D. Cone1
1
Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201, USA
2
Department of Pediatric Endocrinology, Oregon Health Sciences University CDRCP, Portland, Oregon 97201, USA
3
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA
Correspondence should be addressed to Roger D. Cone cone@ohsu.edu
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.
