Chen H Y, Trumbauer M E, Chen A S, Weingarth D T, Adams J R, Frazier E G, Shen Z, Marsh D J, Feighner S D, Guan X-M, Ye Z, Nargund R P, Smith R G, Van der Ploeg L H T, Howard A D, MacNeil D J, Qian S
Department of Metabolic Disorders, Merck Research Laboratories, P.O. Box 2000, RY80T-150, Rahway, New Jersey 07065, USA.
Endocrinology. 2004 Jun;145(6):2607-12. doi: 10.1210/en.2003-1596. Epub 2004 Feb 12.
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 neuropeptide Y (NPY) and agouti-related protein (AgRP) in the central nervous system. These include intracerebroventricular 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 nonpeptide 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. Although deletion of either NPY or AgRP caused only a modest or nondetectable 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.
胃饥饿素是一种由胃产生的促食欲激素，作为肥胖控制的潜在靶点引起了极大关注。药理学证据表明，胃饥饿素对食物摄入的影响是由中枢神经系统中的神经肽Y（NPY）和刺鼠相关蛋白（AgRP）介导的。这些证据包括脑室内注射抗体以中和NPY和AgRP，以及应用NPY Y1受体拮抗剂，该拮抗剂可阻断胃饥饿素的一些促食欲作用。在此，我们描述了用胃饥饿素或口服活性非肽胃饥饿素激动剂治疗Agrp（-/-）；Npy（-/-）和Mc3r（-/-）；Mc4r（-/-）双敲除小鼠以及Npy（-/-）和Agrp（-/-）单敲除小鼠的情况。数据表明，NPY和AgRP是胃饥饿素促食欲作用所必需的，并且黑皮质素途径参与胃饥饿素信号传导。我们的结果概述了NPY和AgRP途径之间的功能相互作用。虽然单独缺失NPY或AgRP仅产生适度或无法检测到的影响，但两种配体的缺失完全消除了胃饥饿素的促食欲作用。我们的结果确立了NPY和AgRP在体内的促食欲功能，介导了胃饥饿素的作用。
