title: Effects of leptin and melanocortin signaling interactions on pubertal development and reproduction.
abstract: Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agouti-related peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Davelene D
authors.initials: DD
authors.lastname: Israel
authors.forename: Sharone
authors.initials: S
authors.lastname: Sheffer-Babila
authors.forename: Carl
authors.initials: C
authors.lastname: de Luca
authors.forename: Young-Hwan
authors.initials: YH
authors.lastname: Jo
authors.forename: Shun Mei
authors.initials: SM
authors.lastname: Liu
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xia
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Spergel
authors.forename: Siok L
authors.initials: SL
authors.lastname: Dun
authors.forename: Nae J
authors.initials: NJ
authors.lastname: Dun
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
mesh_terms: D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002452:Cell Count; D004958:Estradiol / Q000097:blood; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D010053:Ovary / Q000378:metabolism; D011374:Progesterone / Q000097:blood; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism*; D012741:Sexual Maturation / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D054369:Agouti-Related Protein; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D011374:Progesterone; D004958:Estradiol