Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue

Endocrinology. 2007 Apr;148(4):1550-60. doi: 10.1210/en.2006-1389. Epub 2006 Dec 28.


The central melanocortin 4 receptor (MC4R) plays a critical role in energy homeostasis, although little is known regarding its role in the regulation of adaptive thermogenesis of brown adipose tissue (BAT). Here we show using retrograde transsynaptic tracing with attenuated pseudorabies virus coupled with dual-label immunohistochemistry that specific subsets of MC4R-expressing neurons in multiple nuclei of the central nervous system known to regulate sympathetic outflow polysynaptically connect with interscapular BAT (IBAT). Furthermore, we show that MC4R-/- and agouti-related peptide-treated mice are defective in HF diet-induced up-regulation of uncoupling protein 1 in IBAT. Additionally, MC4R-/- mice exposed to 4 C for 4 h exhibit a defect in up-regulation of uncoupling protein 1 levels in IBAT. Our results provide a neuroanatomic substrate for MC4R regulating sympathetically mediated IBAT thermogenesis and demonstrate that the MC4R is critically required for acute high-fat- and cold-induced IBAT thermogenesis.

Publication types

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

MeSH terms

  • Acclimatization / physiology*
  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism
  • Adipose Tissue, Brown / physiology*
  • Agouti-Related Protein
  • Animals
  • Central Nervous System / chemistry
  • Cold Temperature
  • Diet, Atherogenic
  • Herpesvirus 1, Suid
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Ion Channels / metabolism
  • Male
  • Melanocortins / metabolism
  • Melanocortins / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondrial Proteins / metabolism
  • Models, Biological
  • Receptor, Melanocortin, Type 4 / genetics
  • Receptor, Melanocortin, Type 4 / metabolism
  • Receptor, Melanocortin, Type 4 / physiology*
  • Thermogenesis / physiology*
  • Uncoupling Protein 1


  • Agouti-Related Protein
  • Intercellular Signaling Peptides and Proteins
  • Ion Channels
  • Melanocortins
  • Mitochondrial Proteins
  • Receptor, Melanocortin, Type 4
  • Ucp1 protein, mouse
  • Uncoupling Protein 1