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Des-Acyl Ghrelin Induces Food Intake by a Mechanism Independent of the Growth Hormone Secretagogue Receptor

Department of Internal Medicine (K.T., H.Y., Y.D., M.S.M., T.SH., T.K., M.N.), Miyazaki Medical College, University of Miyazaki, Miyazaki 889-1692, Japan; Department of Veterinary Physiology (N.M.), University of Miyazaki, Miyazaki 889-2151, Japan; Huffington Center on Aging (Y.S., R.G.S.), Baylor College of Medicine, Texas 77030; Department of Pharmacology (A.Y., T.SA.), University of Tsukuba, Ibaraki 305-8575, Japan; and National Cardiovascular Center Research Institute (M.M., 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, Miyazaki University, Kiyotake, Miyazaki 889-1692, Japan. E-mail: nakazato{at}med.miyazaki-u.ac.jp.

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.

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