title: Ghrelin-induced food intake is mediated via the orexin pathway.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Miyazaki Medical College, Miyazaki 889-1692, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Toshinai
authors.forename: Yukari
authors.initials: Y
authors.lastname: Date
authors.forename: Noboru
authors.initials: N
authors.lastname: Murakami
authors.forename: Mitsushi
authors.initials: M
authors.lastname: Shimada
authors.forename: Muhtashan S
authors.initials: MS
authors.lastname: Mondal
authors.forename: Takuya
authors.initials: T
authors.lastname: Shimbara
authors.forename: Jian-Lian
authors.initials: JL
authors.lastname: Guan
authors.forename: Qing-Ping
authors.initials: QP
authors.lastname: Wang
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Funahashi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Seiji
authors.initials: S
authors.lastname: Shioda
authors.forename: Shigeru
authors.initials: S
authors.lastname: Matsukura
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
mesh_terms: 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
chemical_list: 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