Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor.
Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and GH secretion via interactions with the GH secretagogue type 1a receptor (GHS-R1a), the functionally active form of the GHS-R. Ghrelin molecules exist in the stomach and hypothalamus as two major endogenous forms, a form acylated at serine 3 (ghrelin) and a des-acylated form (des-acyl ghrelin). Acylation is indispensable for the binding of ghrelin to the GHS-R1a. Ghrelin enhances feeding via the neuronal pathways of neuropeptide Y and orexin, which act as orexigenic peptides in the hypothalamus. We here studied the effect of des-acyl ghrelin on feeding behavior. Intracerebroventricular (icv) administration of rat des-acyl ghrelin to rats or mice fed ad libitum stimulated feeding during the light phase; neither ip nor icv administration of des-acyl ghrelin to fasting mice suppressed feeding. The icv administration of des-acyl ghrelin induced the expression of Fos, a marker of neuronal activation, in orexin-expressing neurons of the lateral hypothalamic area, but not neuropeptide Y-expressing neurons of the arcuate nucleus. Peripheral administration of des-acyl ghrelin to rats or mice did not affect feeding. Although icv administration of ghrelin did not induce food intake in GHS-R-deficient mice, it did in orexin-deficient mice. In contrast, icv administration of des-acyl ghrelin stimulated feeding in GHS-R-deficient mice, but not orexin-deficient mice. Des-acyl ghrelin increased the intracellular calcium concentrations in isolated orexin neurons. Central des-acyl ghrelin may activate orexin-expressing neurons, perhaps functioning in feeding regulation through interactions with a target protein distinct from the GHS-R.
Department of Internal Medicine, Miyazaki Medical College, University of Miyazaki, Japan.
Koji
K
Toshinai
Hideki
H
Yamaguchi
Yuxiang
Y
Sun
Roy G
RG
Smith
Akihiro
A
Yamanaka
Takeshi
T
Sakurai
Yukari
Y
Date
Muhtashan S
MS
Mondal
Takuya
T
Shimbara
Takashi
T
Kawagoe
Noboru
N
Murakami
Mikiya
M
Miyazato
Kenji
K
Kangawa
Masamitsu
M
Nakazato
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003600:Cytosol / Q000378:metabolism; D005247:Feeding Behavior; D005753:Gastric Mucosa / Q000378:metabolism; D054439:Ghrelin; D013006:Growth Hormone / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009068:Movement; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D064446:Orexin Receptors; D000068797:Orexins; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D054440:Receptors, Ghrelin; D018013:Receptors, Neuropeptide; D013997:Time Factors
D054439:Ghrelin; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D036361:Peptide Hormones; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D043562:Receptors, G-Protein-Coupled; D054440:Receptors, Ghrelin; D018013:Receptors, Neuropeptide; C422650:ghrelin, des-n-octanoyl; D013006:Growth Hormone; D002118:Calcium