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This version published online on February 12, 2004
Endocrinology, doi:10.1210/en.2003-1596
A more recent version of this article appeared on June 1, 2004
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Submitted on November 24, 2003
Accepted on February 2, 2004

Orexigenic Action of Peripheral Ghrelin is Mediated by Neuropeptide Y (NPY) and Agouti-Related Protein (AgRP)

H. Y. Chen*, M. E. Trumbauer, A. S. Chen, D. T. Weingarth, J. R. Adams, E. G. Frazier, Z. Shen, D. J. Marsh, S. D. Feighner, X. -M. Guan, Z. Ye, R. P. Nargund, R. G. Smith, L. H.T. Van der Ploeg, A. D. Howard, D. J. MacNeil, and S. Qian

Departments of Metabolic Disorders (H.Y.C., M.E.T., A.S.C., D.T.W., J.R.A., E.G.F., Z.S., D.J.M., S.D.F., X.-M. G., L.H.T.V., A.D.H., D.J.M., S.Q.) and Medicinal Chemistry (Z.Y., R.P.N.), Merck Research Laboratories, Rahway, NJ 07065; Huffington Center on Aging, (R.G.S.) Baylor College of Medicine, Houston, Tx 77030

* To whom correspondence should be addressed. E-mail: howard chen{at}merck.com.

Ghrelin, a stomach-derived orexigenic hormone, has stimulated great interest as a potential target for obesity control. Pharmacological evidence indicates that ghrelin's effects on food intake are mediated by NPY and AgRP in the CNS. These include intracerebroventricular (icv) application of antibodies to neutralize NPY and AgRP, and the application of an NPY Y1 receptor antagonist, which blocks some of the orexigenic effects of ghrelin. Here we describe treatment of Agrp-/-;Npy-/- and Mc3r-/-;Mc4r-/- double knockout mice as well as Npy-/- and Agrp-/- single knockout mice with either ghrelin or an orally-active non-peptide ghrelin agonist. The data demonstrate that NPY and AgRP are required for the orexigenic effects of ghrelin, as well as the involvement of the melanocortin pathway in ghrelin signaling. Our results outline a functional interaction between the NPY and AgRP pathways. While deletion of either NPY or AgRP caused only a modest or non-detectable effect, ablation of both ligands completely abolished the orexigenic action of ghrelin. Our results establish an in vivo orexigenic function for NPY and AgRP, mediating the effect of ghrelin.
Key words: Ghrelin • AgRP • NPY • Melanocortin




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