Identification of hypothalamic nuclei involved in the orexigenic effect of melanin-concentrating hormone.
The hypothalamic neuropeptide melanin-concentrating hormone (MCH) increases feeding when injected intracerebroventricularly in rats. To identify the hypothalamic nuclei responsible for the orexigenic effect, we injected the peptide into discrete hypothalamic nuclei known to express the MCH receptor, MCH1R. MCH (0.6 nmol) elicited a rapid and significant increase in feeding in satiated rats following injection into the arcuate nucleus (0-1 h: 421 +/- 60%; P < 0.01). An elevation in feeding was also observed following injection into the paraventricular nucleus, which was sustained up to 4 h post injection (0-4 h: 218 +/- 29%; P < 0.01). A significant increase in feeding during this time period was also observed following injection into the dorsomedial nucleus (0-4 h: 155 +/- 12%; P < 0.05). No significant alteration in feeding was observed following injection into the supraoptic nucleus, lateral hypothalamic area, medial preoptic area, anterior hypothalamic area, or ventromedial nucleus of the hypothalamus. To identify the neurotransmitters that may be potentially involved in this effect, we examined their release from hypothalamic explants in vitro following exogenous MCH administration. MCH (1 micro M) increased the release of the orexigenic neurotransmitters neuropeptide Y (37.8 +/- 6.0 fmol/explant vs. basal 30.2 +/- 4.3 fmol/explant; P < 0.05) and agouti-related peptide (4.1 +/- 0.6 fmol/explant vs. basal 2.4 +/- 0.2 fmol/explant; P < 0.05) and decreased the release of the anorectic neurotransmitters alpha-MSH (41.7 +/- 6.8 fmol/explant vs. basal 65.9 +/- 11.0 fmol/explant; P < 0.01) and cocaine- and amphetamine-regulated transcript (112.3 +/- 12.4 fmol/explant vs. basal 167.4 +/- 13.0 fmol/explant; P < 0.001). These studies suggest that the orexigenic effect of MCH may be mediated via activation or inhibition of these feeding circuits within the arcuate nucleus and paraventricular nucleus of the hypothalamus.
Abbott
Caroline R
CR
Endocrine Unit, Imperial College London, Hammersmith Campus, London W12 ONN, United Kingdom.
Kennedy
Adam R
AR
Wren
Alison M
AM
Rossi
Michela
M
Murphy
Kevin G
KG
Seal
Leighton J
LJ
Todd
Jeannie F
JF
Ghatei
Mohammad A
MA
Small
Caroline J
CJ
Bloom
Stephen R
SR
D054369:Agouti-Related Protein; D000818:Animals; D001066:Appetite / Q000187:drug effects / Q000502:physiology; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D007028:Hypothalamic Hormones / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D008543:Melanins / Q000494:pharmacology*; D008845:Microinjections; D009478:Neuropeptide Y / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D010907:Pituitary Hormones / Q000494:pharmacology*; D011506:Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000521:alpha-MSH / Q000378:metabolism
D054369:Agouti-Related Protein; D007028:Hypothalamic Hormones; D036341:Intercellular Signaling Peptides and Proteins; D008543:Melanins; D009478:Neuropeptide Y; D010907:Pituitary Hormones; D011506:Proteins; D000521:alpha-MSH; C019463:melanin-concentrating hormone