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Central Administration of Ghrelin and Agouti-Related Protein (83–132) Increases Food Intake and Decreases Spontaneous Locomotor Activity in Rats

Pharmacology (M.T.-C., N.V.), RheoScience A/S, Copenhagen Denmark; Institute for Zoo and Wildlife Research (S.O.), Berlin, Germany; Neuroendocrine Unit (M.B.), Innenstadt University Hospital, Munich, Germany; Departments of Obstetrics and Gynaecology, Neurobiology, and Neurosurgery (T.L.H.), Yale University School of Medicine, New Haven, Connecticut 06520; Obesity Research Center (M.T.), Department of Psychiatry, University of Cincinnati Genome Research Institute, Cincinnati, Ohio; and German Institute of Human Nutrition (S.O., M.T.), 14556 Postdam Rebrücke, Germany

Address all correspondence and requests for reprints to: Mads Tang-Christensen, M.D., Ph.D., Pharmacology, RheoScience A/S, Glerupvej 2, DK-2610 Roedovre, Denmark. E-mail: mtc{at}rheoscience.com.

Ghrelin was recently identified as an endogenous ligand of the GH secretagogue receptor. The novel peptide hormone is produced by gastric A-like cells, and circulating levels rise before feeding, suggestive of ghrelin as an endogenous hunger factor. ghrelin stimulates food intake and promotes adiposity after peripheral or central administration, likely by activating hypothalamic neurons expressing the orexigenic neuropeptides neuropeptide Y (NPY) and agouti-related protein (AGRP). To examine whether ghrelin-induced feeding resembles NPY and AGRP [AGRP fragment (83–132)] induced orexia, we compared the short- and long-term orexigenic capacity of the three peptides. A single intracerebroventricular injection of ghrelin (0.2, 1.0, and 5.0 µg) increased food intake in a dose-dependent manner. A prolonged and uncompensated increase in feeding was seen after the highest dose of ghrelin. The prolonged effects on feeding (+72 h) closely resembled those of AGRP (83–132) but not NPY. Surprisingly, ghrelin injections reduced overall locomotor activity by 20% during the first 24-h observation period. AGRP (83–132) had similar effects on locomotor behavior, whereas NPY had no effect. In summary, ghrelin causes long-term increases of food intake and, like AGRP, plays a previously unknown role as a suppressor of spontaneous physical activity. Expanding the current model of food intake control to include mechanisms regulating physical activity may promote our understanding of two major etiological factors causing obesity.

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