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Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area.

The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R). The lateral hypothalamic area (LHA) receives dense melanocortinergic inputs from the arcuate nucleus of the hypothalamus and regulates multiple processes including food intake, reward behaviors, and autonomic function. By using a mouse line in which green fluorescent protein (GFP) is expressed under control of the MC4R gene promoter, we systemically investigated MC4R signaling in the LHA by combining double immunohistochemistry, electrophysiology, and retrograde tracing techniques. We found that LHA MC4R-GFP neurons coexpress neurotensin as well as the leptin receptor but do not coexpress other peptide neurotransmitters found in the LHA including orexin, melanin-concentrating hormone, and nesfatin-1. Furthermore, electrophysiological recording demonstrated that leptin, but not the MC4R agonist melanotan II, hyperpolarizes the majority of LHA MC4R-GFP neurons in an ATP- sensitive potassium channel-dependent manner. Retrograde tracing revealed that LHA MC4R-GFP neurons do not project to the ventral tegmental area, dorsal raphe nucleus, nucleus accumbens, and spinal cord, and only limited number of neurons project to the nucleus of the solitary tract and parabrachial nucleus. Our findings provide new insights into MC4R signaling in the LHA and its potential implications in homeostatic regulation of body energy balance.

Pubmed ID: 22605619


  • Cui H
  • Sohn JW
  • Gautron L
  • Funahashi H
  • Williams KW
  • Elmquist JK
  • Lutter M


The Journal of comparative neurology

Publication Data

December 15, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: K01DK087780
  • Agency: NIMH NIH HHS, Id: K08 MH084058
  • Agency: NIMH NIH HHS, Id: MH084058-01A1
  • Agency: NIDDK NIH HHS, Id: R01DK53301
  • Agency: NIDDK NIH HHS, Id: RL1DK081185

Mesh Terms

  • Animals
  • Calcium-Binding Proteins
  • Cell Count
  • Cholera Toxin
  • Circadian Rhythm
  • DNA-Binding Proteins
  • Green Fluorescent Proteins
  • Humans
  • Hypothalamic Area, Lateral
  • Intracellular Signaling Peptides and Proteins
  • Leptin
  • Male
  • Membrane Potentials
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins
  • Neural Pathways
  • Neuroanatomy
  • Neurons
  • Neuropeptides
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Receptor, Melanocortin, Type 4
  • STAT3 Transcription Factor
  • Stilbamidines