A Neural Basis for melanocortin-4 Receptor-Regulated Appetite

Nat Neurosci. 2015 Jun;18(6):863-71. doi: 10.1038/nn.4011. Epub 2015 Apr 27.


Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons of the arcuate nucleus of the hypothalamus (ARC) are oppositely regulated by caloric depletion and coordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) in the paraventricular nucleus of the hypothalamus (PVH). Although this population is critical to energy balance, the underlying neural circuitry remains unknown. Using mice expressing Cre recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVH(MC4R) neurons and further identify these cells as a functional exponent of ARC(AgRP) neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVH(MC4R)→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVH(MC4R)→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for antiobesity drug development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agouti-Related Protein / physiology
  • Animals
  • Anti-Obesity Agents / pharmacology
  • Appetite / drug effects*
  • Energy Metabolism / drug effects
  • Feeding Behavior / drug effects
  • Food Deprivation
  • Food Preferences / drug effects
  • Hunger / physiology
  • Mice
  • Neural Pathways / drug effects
  • Neurons / drug effects
  • Neurons / physiology
  • Paraventricular Hypothalamic Nucleus / drug effects
  • Paraventricular Hypothalamic Nucleus / physiology
  • Pro-Opiomelanocortin / physiology
  • Receptor, Melanocortin, Type 4 / antagonists & inhibitors*
  • Satiation / physiology


  • Agouti-Related Protein
  • Anti-Obesity Agents
  • Receptor, Melanocortin, Type 4
  • Pro-Opiomelanocortin