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Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

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Science  03 Oct 1997:
Vol. 278, Issue 5335, pp. 135-138
DOI: 10.1126/science.278.5335.135

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Abstract

Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.

  • * These authors contributed equally to this work.

  • To whom correspondence should be addressed at Beckman Center B271A, Stanford University School of Medicine, Stanford, CA 94305–5323, USA. E-mail: gbarsh{at}cmgm.stanford.edu.

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