Dynamic regulation of hypothalamic neuropeptide gene expression and food intake by melanocortin analogues and reversal with melanocortin-4 receptor antagonist.
Melanocortins are known to be involved in the inhibition of food intake and energy metabolism. Acute and chronic intracerebroventricular administration of several different analogues of alpha-MSH, such as alpha-MSH, NDP-MSH, alpha-MSH-ND, [Gln(6)]alpha-MSH-ND, and [Lys(6)]alpha-MSH-ND, which were substituted in the position of His(6) with Gln and Lys, and cyclic16k-MSH to C57J/BL6 mice resulted in a significant inhibition of both time course food intake and body weight gain, compared to the saline-administered control. However, [Gln(6)]alpha-MSH-ND(6-10), the truncated form of [Gln(6)]alpha-MSH-ND, had no inhibitory effects on food intake. In situ hybridization analysis revealed that the expression levels of AGRP and NPY in the hypothalamus were significantly and rapidly diminished while POMC expression was strongly induced by [Gln(6)]alpha-MSH-ND. Administration of JKC-363, a selective MC4R-specific antagonist, coupled with [Gln(6)]alpha-MSH-ND, specifically reversed the [Gln(6)]alpha-MSH-ND-induced inhibition of food intake, but also reversed the hypothalamic expression levels of neuropeptides such as AGRP, NPY, MCH, and POMC, which suggests [Gln(6)]alpha-MSH-ND can function as a selective MC4R agonist.
Kim
Ryang Yeo
RY
School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea.
Shin
Seung Woo
SW
Kim
Byung Jin
BJ
Lee
Weontae
W
Baik
Ja-Hyun
JH
D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000235:genetics*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D009479:Neuropeptides; D010446:Peptide Fragments; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D009074:Melanocyte-Stimulating Hormones