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      Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.

      Science (New York, N.Y.)

      Adrenal Glands, metabolism, Amino Acid Sequence, Animals, Female, Humans, Hypothalamus, Male, Melanocyte-Stimulating Hormones, antagonists & inhibitors, pharmacology, Melanophores, Mice, Mice, Inbred C57BL, Mice, Inbred CBA, Mice, Obese, Mice, Transgenic, Molecular Sequence Data, Obesity, etiology, Organophosphorus Compounds, Proteins, chemistry, genetics, physiology, RNA, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Receptors, Corticotropin, Receptors, Peptide, Recombinant Proteins, Signal Transduction, Xenopus

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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.

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          9311920

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