c931e56e-ec7a-4e70-9902-5363983d985d
title
Melanin-concentrating hormone receptor mutations and human obesity: functional analysis.
be6da078-cae5-450f-ba71-8f3af30545ea
abstract
Melanin-concentrating hormone (MCH) , a neuropeptide highly expressed in the lateral hypothalamus, has an important role in the regulation of energy balance and body weight in rodents. We examined whether mutations in the two known MCH receptors might be associated with obesity-related phenotypes in humans. Among 106 subjects with severe early onset obesity and a history of hyperphagia, we found two missense variants in  MCHR1 :  Y181H  and  R248Q . Neither of these was found in 192 normal weight controls.  R248Q  cosegregated with obesity across two generations; family data were unavailable for  Y181H . When expressed in HEK293 cells,  R248Q  showed no evidence of constitutive activation or ligand hypersensitivity for extracellular signal-regulated kinase phosphorylation. In addition,  R248Q  showed no enhanced suppression of cAMP generation. Two common single-nucleotide polymorphisms were found to be in linkage disequilibrium:  g.-114A>G  and  c.39C>T . No association between either of these single-nucleotide polymorphisms and obesity-related phenotypes was found among a population cohort of 541 whites. Only two rare noncoding variants were found in  MCHR2 . In conclusion, mutations in the MCH receptors are not commonly found in humans with severe early onset obesity. Clarification of the relationship of these variants to obesity must await study in other populations and/or in genetically modified mice.