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
- Mitsuyo Shintani,
- Yoshihiro Ogawa,
- Ken Ebihara,
- Megumi Aizawa-Abe,
- Fumiko Miyanaga,
- Kazuhiko Takaya,
- Tatsuya Hayashi,
- Gen Inoue,
- Kiminori Hosoda,
- Masayasu Kojima,
- Kenji Kangawa and
- Kazuwa Nakao
- From the Department of Medicine and Clinical Science (M.S., Y.O., K.E., M.A.-A., F.M., K.T., T.H., G.I., K.H., K.N.), Kyoto University Graduate School of Medicine, Kyoto; and the Department of Biochemistry (M.K., K.K.), National Cardiovascular Center Research Institute, Osaka, Japan.
- Address correspondence and reprint requests to Yoshihiro Ogawa, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 Japan. E-mail: ogawa{at}kuhp.kyoto-u.ac.jp .
Abstract
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) (∼ 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 μg/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.
Footnotes
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Posted on the World Wide Web at www.diabetes.org/diabetes on <<insert date> 2001.
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AGRP, agouti-related protein; GH, growth hormone; GHRH, growth hormone-releasing hormone; GHS, growth hormone secretagogue; GHS-R, GHS receptor; ICV, intracerebroventricular; NPY, neuropeptide Y.
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- Accepted November 9, 2000.
- Received August 16, 2000.
- by the American Diabetes Association, Inc.
