The most frequent genetic cause of obesity in humans is melanocortin-4 receptor (MC4R) mutations. MC4R has an effect on appetite: when MC4R is activated by its ligand amelanocyte-stimulat-ing hormone (a-MHC) appetite is suppressed. When its activity is suppressed by its ligand agouti-related protein (AGRP), appetite is enhanced. MC4R also has a low level activation, resulting in appetite suppression, even in the absence of a-MHC. Given its pivotal role in energy homeostasis, MC4R is considered a viable therapeutic target for combat-ing obesity. The parts of the MC4R protein that is required for a-MHC activation are well known, but those required for its constitutive activity and the biologic importance of this low level of MC4R activity remain uncertain.

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.

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Contact: Laurie Goodman
press_releases@the-jci.org
212-342-4159
Journal of Clinical Investigation
15-Oct-2004

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