The melanocortin agonist Melanotan-II reduces the orexigenic and adipogenic effects of neuropeptide Y (NPY) but does not affect the NPY-driven suppressive effects on the gonadotropic and somatotropic axes in the male rat.
Neuropeptide Y (NPY) is a strong orexigenic neurotransmitter also known to modulate several neuroendocrine axes. alpha-Melanocyte-stimulating hormone (MSH) is an essential anorectic neuropeptide, acting on hypothalamic MC3/4 receptor subtypes. When given as an intracerebroventricular bolus injection, Melanotan-II (MT-II), a non selective MC receptor agonist, inhibits feeding, suppresses the NPY orexigenic action, and reduces basal insulinaemia. We evaluated the effects of a 7-day central infusion of MT-II (15 nmol/day) given either alone or in association with NPY (5 nmol/day) in male Sprague-Dawley rats. MT-II produced almost full anorexia for 1-2 days but then feeding gradually returned to normal despite continued MT-II infusion. When coinfused with NPY, MT-II also produced the same initial anorectic episode but then maintained feeding to upper normal levels, thus cancelling the hyperphagia driven by NPY. Whereas NPY infusion produced a doubling of fat pad weight, MT-II reduced adiposity by a factor of two compared to pair-fed rats, and vastly curtailed the NPY-driven increase in fat pad weight. MT-II infusion also significantly curtailed the NPY-induced rise in insulin and leptin secretions. NPY infusion significantly inhibited hypothalamic pro-opiomelanocortin mRNA expression, most likely cancelling the alpha-MSH anorectic activity. As expected from previous studies, chronic NPY infusion strongly inhibited both the gonadotropic and somatotropic axes, and coinfusion of MT-II did not reverse these NPY-driven effects, in sharp contrast with that seen for the metabolic data. MT-II infusion alone had little effect on these axes. In conclusion, chronic MT-II infusion generated a severe but transient reduction in feeding, suggesting an escape phenomenon, and clearly reduced fat pad size. When coinfused with NPY, MT-II was able to cancel most of the NPY effects on feeding, but not those on the neuroendocrine axes. It appears therefore that, as expected, NPY and alpha-MSH closely interact in the control of feeding, whereas the neural pathways by which NPY affects growth and reproduction are distinct and not sensitive to MC peptide modulation.
Raposinho
P D
PD
Division of Development and Growth, Department of Pediatrics, University of Geneva School of Medicine, Geneva, Switzerland.
White
R B
RB
Aubert
M L
ML
D017667:Adipocytes / Q000502:physiology; D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D004326:Drinking / Q000187:drug effects; D004347:Drug Interactions; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D012739:Gonadal Steroid Hormones / Q000502:physiology; D013007:Growth Hormone-Releasing Hormone / Q000235:genetics; D007031:Hypothalamus / Q000187:drug effects* / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics / Q000494:pharmacology*; D009479:Neuropeptides / Q000502:physiology; D009765:Obesity / Q000503:physiopathology; D000068797:Orexins; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011333:Pro-Opiomelanocortin / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015430:Weight Gain / Q000187:drug effects; D000521:alpha-MSH / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology*
D002352:Carrier Proteins; D012739:Gonadal Steroid Hormones; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D010456:Peptides, Cyclic; C079282:melanotan-II; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone