title: Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area.
abstract: 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.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9127, USA.
authors.forename: Huxing
authors.initials: H
authors.lastname: Cui
authors.forename: Jong-Woo
authors.initials: JW
authors.lastname: Sohn
authors.forename: Laurent
authors.initials: L
authors.lastname: Gautron
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Funahashi
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Williams
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Michael
authors.initials: M
authors.lastname: Lutter
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002452:Cell Count; D002772:Cholera Toxin / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007026:Hypothalamic Area, Lateral / Q000166:cytology* / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020738:Leptin / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000502:physiology*; D009445:Neuroanatomy; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D000080866:Nucleobindins; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013266:Stilbamidines / Q000378:metabolism
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; C000630650:NUCB2 protein, human; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C000630651:Nucb1 protein, mouse; D000080866:Nucleobindins; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D050796:STAT3 Transcription Factor; D013266:Stilbamidines; D049452:Green Fluorescent Proteins; D002772:Cholera Toxin