Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.
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.
Ollmann
M M
MM
Department of Pediatrics, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Wilson
B D
BD
Yang
Y K
YK
Kerns
J A
JA
Chen
Y
Y
Gantz
I
I
Barsh
G S
GS
D000311:Adrenal Glands / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008547:Melanophores / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008820:Mice, Obese; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009765:Obesity / Q000209:etiology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014981:Xenopus
D009943:Organophosphorus Compounds; D011506:Proteins; D044104:Receptor, Melanocortin, Type 3; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D018000:Receptors, Peptide; D011994:Recombinant Proteins; C107353:CGP 54626; D012313:RNA; D009074:Melanocyte-Stimulating Hormones