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

Nat Neurosci. 2001 Jun;4(6):605-11. doi: 10.1038/88423.


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.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipose Tissue, Brown / physiology
  • Animals
  • Crosses, Genetic
  • Dietary Fats / pharmacology*
  • Energy Metabolism
  • Feeding Behavior
  • Female
  • Homeostasis
  • Hyperphagia / genetics*
  • Leptin / deficiency
  • Leptin / genetics
  • Leptin / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Physical Exertion
  • Receptor, Melanocortin, Type 3
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin / deficiency
  • Receptors, Corticotropin / genetics
  • Receptors, Corticotropin / physiology*
  • Reference Values
  • Thermogenesis
  • Weight Gain


  • Dietary Fats
  • Leptin
  • Receptor, Melanocortin, Type 3
  • Receptor, Melanocortin, Type 4
  • Receptors, Corticotropin