Ghrelin-induced food intake is mediated via the orexin pathway.
The hypothalamus regulates energy intake by integrating the degree of starvation or satiation with the status of the environment through a variety of neuronal and blood-derived signals. Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates feeding and GH secretion. Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY) and agouti-related protein systems. The interaction between ghrelin and other hypothalamic orexigenic peptides, however, has not been clarified. Here, we investigated the anatomical interactions and functional relationship between ghrelin and two orexigenic peptides, orexin and melanin-concentrating hormone (MCH), present in the lateral hypothalamus. Ghrelin-immunoreactive axonal terminals made direct synaptic contacts with orexin-producing neurons. Intracerebroventricular administration of ghrelin induced Fos expression, a marker of neuronal activation, in orexin-producing neurons but not in MCH-producing neurons. Ghrelin remained competent to induce Fos expression in orexin-producing neurons following pretreatment with anti-NPY IgG. Pretreatment with anti-orexin-A IgG and anti-orexin-B IgG, but not anti-MCH IgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-IgGs. Ghrelin-induced feeding was also suppressed in orexin knockout mice. This study identifies a novel hypothalamic pathway that links ghrelin and orexin in the regulation of feeding behavior and energy homeostasis.
Toshinai
Koji
K
Department of Internal Medicine, Miyazaki Medical College, Miyazaki 889-1692, Japan.
Date
Yukari
Y
Murakami
Noboru
N
Shimada
Mitsushi
M
Mondal
Muhtashan S
MS
Shimbara
Takuya
T
Guan
Jian-Lian
JL
Wang
Qing-Ping
QP
Funahashi
Hisayuki
H
Sakurai
Takeshi
T
Shioda
Seiji
S
Matsukura
Shigeru
S
Kangawa
Kenji
K
Nakazato
Masamitsu
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D005455:Fluorescent Antibody Technique; D054439:Ghrelin; D007028:Hypothalamic Hormones / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008543:Melanins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D009474:Neurons / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000068797:Orexins; D036361:Peptide Hormones / Q000032:analysis / Q000494:pharmacology*; D010907:Pituitary Hormones / Q000276:immunology / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar
D000906:Antibodies; D002352:Carrier Proteins; D054439:Ghrelin; D007028:Hypothalamic Hormones; D047908:Intracellular Signaling Peptides and Proteins; D008543:Melanins; D009479:Neuropeptides; D000068797:Orexins; D036361:Peptide Hormones; D010907:Pituitary Hormones; D016760:Proto-Oncogene Proteins c-fos; C019463:melanin-concentrating hormone