title: Pivotal roles of alpha-melanocyte-stimulating hormone and the melanocortin 4 receptor in leptin stimulation of prolactin secretion in rats.
abstract: Leptin, the obese gene product, was reported to stimulate prolactin (PRL) secretion, but the neuroendocrine mechanism underlying this hormonal response is largely unknown. Thus, in this study we examined the involvement of several important PRL regulators in the leptin-induced PRL secretion in male rats. Compared with the values in normally fed rats, food deprivation for 3 days significantly decreased both PRL and leptin levels in the plasma. These changes were reverted to normal by a 3-day constant infusion of 75 microg/kg/day of leptin to the fasted rats, while 225 microg/kg/day of leptin further elevated both PRL and leptin levels. These four groups of animals were used for the following experiments. Results of dopamine and serotonin turnover studies in the brain and the pituitary indicated that neither of these biogenic amines plays a primary role in mediating leptin's effects on PRL. Repeated intracerebroventricular injections over 72 h of neutralizing antibodies against vasoactive intestinal peptide, PRL-releasing peptide, or beta-endorphin, did not significantly suppress the leptin actions. However, both the blockade of the melanocortin (MC) 4 receptor (R) and the immunoquenching of brain alpha-melanocyte-stimulating hormone (alpha-MSH) completely abolished the leptin-induced PRL release, and the stimulation of the MC4-R, but not the MC3-R, significantly elevated PRL levels in the fasted rats. These results suggest that alpha-MSH, a cleaved peptide from pro-opiomelanocortin of which synthesis is stimulated by leptin, may be the pivotal neuropeptide in the brain mediating the leptin's stimulatory influence on PRL secretion. It was also suggested that the MC4-R may be the primary subtype of the MC-Rs mediating this action of alpha-MSH.
authors.affiliation: Division of Internal Medicine, Clinical Research Center, International University of Health and Welfare, Otawara, Tochigi, Japan. watah@iuhw.ac.jp
authors.forename: Hajime
authors.initials: H
authors.lastname: Watanobe
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Junkichi
authors.initials: J
authors.lastname: Izumi
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005215:Fasting / Q000502:physiology; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D007028:Hypothalamic Hormones / Q000037:antagonists & inhibitors; D007106:Immune Sera / Q000008:administration & dosage; D007276:Injections, Intraventricular; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009479:Neuropeptides / Q000037:antagonists & inhibitors; D010456:Peptides, Cyclic / Q000008:administration & dosage; D010902:Pituitary Gland / Q000378:metabolism; D011388:Prolactin / Q000097:blood / Q000378:metabolism*; D056690:Prolactin-Releasing Hormone; D051381:Rats; D017208:Rats, Wistar; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000037:antagonists & inhibitors; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001615:beta-Endorphin / Q000037:antagonists & inhibitors; D019825:gamma-MSH / Q000008:administration & dosage
chemical_list: C116941:HS014 cyclic peptide; D007028:Hypothalamic Hormones; D007106:Immune Sera; D020738:Leptin; D009479:Neuropeptides; D010456:Peptides, Cyclic; C534379:Prlh protein, rat; D056690:Prolactin-Releasing Hormone; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; D019825:gamma-MSH; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D014660:Vasoactive Intestinal Peptide; D006897:Hydroxyindoleacetic Acid; D000521:alpha-MSH; D001615:beta-Endorphin; D011388:Prolactin; D004298:Dopamine