To further understanding in these areas, Christian Vaisse and colleagues, from the University of California, San Francisco, made a systematic study of naturally occurring MC4R mutations in obese patients. By genetically transferring normal or mutant versions of the MC4R gene into cells in culture, the authors were able to define a cluster of mutations at the N-terminal end that impaired the constitutive activ-ity of MC4R. Deletion of the N-ter-minal portion of the protein demonstrated that it is required for this basal activity. Further analysis proved that this domain func-tions as an intermolecular self-activating ligand that does not mimic manner in which a-MHC activates MC4R. The work here suggests that in devising therapies for obesity that target MC4R, designing a molecule that provides a low, sustained level of MC4R activation may be a better therapeutic agent for combating obesity than a more powerful activating molecule, which can result in the MC4R receptor becoming desensitized.
TITLE: Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans
AUTHOR CONTACT:
Christian Vaisse
University of California San Francisco, 513 Parnassus Ave, San Francisco, CA 94143, USA
Phone: 415-514-0530; Fax: 415-564-5813; E-mail: vaisse@medicine.ucsf.edu
View the PDF of this article at: http://www.jci.org/cgi/content/full/114/8/1158
Journal
Journal of Clinical Investigation