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Endocrinology Vol. 144, No. 4 1506-1512
Copyright © 2003 by The Endocrine Society

ARTICLE

Ghrelin-Induced Food Intake Is Mediated via the Orexin Pathway

Koji Toshinai, Yukari Date, Noboru Murakami, Mitsushi Shimada, Muhtashan S. Mondal, Takuya Shimbara, Jian-Lian Guan, Qing-Ping Wang, Hisayuki Funahashi, Takeshi Sakurai, Seiji Shioda, Shigeru Matsukura, Kenji Kangawa and Masamitsu Nakazato

Department of Internal Medicine (K.T., Y.D., M.S.M., T.S., S.M., M.N.), Miyazaki Medical College, Miyazaki 889-1692, Japan; Department of Veterinary Physiology (N.M.), University of Miyazaki, Miyazaki 889-2151, Japan; First Department of Internal Medicine (M.S.), Oita Medical University, Oita 879-5593, Japan; Department of Anatomy (J.-L.G., Q.-P.W., H.F., S.S.), Showa University School of Medicine, Tokyo 142-8555, Japan; Department of Pharmacology, University of Tsukuba (T.S.), Ibaraki 305-8575, Japan; and National Cardiovascular Center Research Institute (Y.D., K.K.), Osaka 565-8565, Japan

Address all correspondence and requests for reprints to: Masamitsu Nakazato, M.D., Ph.D. Third Department of Internal Medicine, Miyazaki Medical College, Kiyotake, Miyazaki 889-1692, Japan. E-mail: nakazato{at}post.miyazaki-med.ac.jp.

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.




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