Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway.
Ghrelin, an endogenous ligand for growth hormone secretagogue (GHS) receptor originally isolated from the stomach, occurs in the hypothalamic arcuate nucleus and may play a role in energy homeostasis. Synthetic GHSs have activated the hypothalamic arcuate neurons containing neuropeptide Y (NPY), suggesting the involvement of NPY in some of ghrelin actions. This study was designed to elucidate the role of ghrelin in the regulation of food intake. A single intracerebroventricular (ICV) injection of ghrelin (5-5,000 ng/rat) caused a significant and dose-related increase in cumulative food intake in rats. Ghrelin (500 ng/rat) was also effective in growth hormone-deficient spontaneous dwarf rats. Hypothalamic NPY mRNA expression was increased in rats that received a single ICV injection of ghrelin (500 ng/rat) (approximately 160% of that in vehicle-treated groups, P < 0.05). The ghrelin's orexigenic effect was abolished dose-dependently by ICV co-injection of NPY Y1 receptor antagonist (10-30 microg/rat). The leptin-induced inhibition of food intake was reversed by ICV co-injection of ghrelin in a dose-dependent manner (5-500 ng/rat). Leptin reduced hypothalamic NPY mRNA expression by 35% (P < 0.05), which was abolished by ICV co-injection of ghrelin (500 ng/rat). This study provides evidence that ghrelin is an orexigenic peptide that antagonizes leptin action through the activation of hypothalamic NPY/Y1 receptor pathway.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Japan.
M
M
Shintani
Y
Y
Ogawa
K
K
Ebihara
M
M
Aizawa-Abe
F
F
Miyanaga
K
K
Takaya
T
T
Hayashi
G
G
Inoue
K
K
Hosoda
M
M
Kojima
K
K
Kangawa
K
K
Nakao
D000818:Animals; D004338:Drug Combinations; D054439:Ghrelin; D013006:Growth Hormone / Q000172:deficiency / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007276:Injections, Intraventricular; D020738:Leptin / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics / Q000502:physiology*; D036361:Peptide Hormones; D010455:Peptides / Q000494:pharmacology / Q000502:physiology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D004338:Drug Combinations; D054439:Ghrelin; D020738:Leptin; D009478:Neuropeptide Y; D036361:Peptide Hormones; D010455:Peptides; D012333:RNA, Messenger; D013006:Growth Hormone