Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein
Michael M. Ollmann,
*
Brent D. Wilson,
*
Ying-Kui Yang,
Julie A. Kerns,
Yanru Chen,
Ira Gantz,
Gregory S. Barsh
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.
M. M. Ollmann, B. D. Wilson, J. A. Kerns, Y. Chen,
G. S. Barsh, Departments of Pediatrics and Genetics and the Howard
Hughes Medical Institute, Stanford University School of Medicine,
Stanford, CA 94305, USA.
Y.-K. Yang and I. Gantz, Department of Surgery, University of Michigan
School of Medicine, Ann Arbor, MI 48109-0682, USA.
*
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.
