title: Melanocortins mimic the effects of leptin to restore reproductive function in lean hypogonadotropic ewes.
abstract: OBJECTIVE
  Leptin restores gonadotropic function in lean hypogonadotropic animals by an unknown mechanism. We aimed to test the hypothesis that restoration of gonadotropic function is a result of an upregulation of central acetylated melanocortin production.
  
  
  RESULTS
  Lean ovariectomised (OVX) ewes received intracerebroventricular (i.c.v.) infusions of leptin (or vehicle) for 3 days, which upregulated proopiomelanocortin (POMC) mRNA and restored pulsatile luteinizing hormone (LH) secretion. A melanocortin agonist (MTII), but not naloxone treatment, reinstated pulsatile LH secretion in lean OVX ewes. We treated (i.c.v.) lean OVX ewes with leptin (or vehicle) and measured peptide levels and post-translational modification in the arcuate nucleus (ARC). Levels of beta-endorphin (beta-END) were lower in lean animals, with no effect of leptin treatment. Desacetyl-alpha-MSH was the predominant form of alpha-melanocyte-stimulating hormone (alpha-MSH) in the ARC and levels were similar in all groups. In another group of lean and normal-weight OVX ewes, we measured the different forms of alpha-MSH in ARC, hypothalamus (ARC-removed) and the preoptic area (POA). Acetylated alpha-MSH levels were lower in lean animals in the terminal beds of the hypothalamus and POA but not the ARC.
  
  
  CONCLUSIONS
  Leptin corrects the hypogonadotropic state in the lean condition by upregulation of POMC gene expression, and may increase transport and acetylation of melanocortins to target cells in the brain. Melanocortin treatment restores LH secretion in lean animals.
authors.affiliation: Department of Physiology, Monash University, Monash, Vic, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Backholer
authors.forename: Marissa
authors.initials: M
authors.lastname: Bowden
authors.forename: Kevin
authors.initials: K
authors.lastname: Gamber
authors.forename: Christian
authors.initials: C
authors.lastname: Bjørbaek
authors.forename: Javed
authors.initials: J
authors.lastname: Iqbal
authors.forename: Iain J
authors.initials: IJ
authors.lastname: Clarke
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D002491:Central Nervous System Agents / Q000494:pharmacology*; D005260:Female; D020249:Hormone Replacement Therapy; D007006:Hypogonadism / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007031:Hypothalamus / Q000187:drug effects / Q000503:physiopathology; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D053486:Melanocortins / Q000494:pharmacology*; D010052:Ovariectomy; D011301:Preoptic Area / Q000187:drug effects / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012098:Reproduction / Q000187:drug effects* / Q000502:physiology; D012756:Sheep; D013851:Thinness; D000521:alpha-MSH / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism
chemical_list: D002491:Central Nervous System Agents; D020738:Leptin; D053486:Melanocortins; D012333:RNA, Messenger; D000521:alpha-MSH; D001615:beta-Endorphin; D011333:Pro-Opiomelanocortin; D007986:Luteinizing Hormone