Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis.

The melanocortin-4 receptor gene (MC4R) has intensively been analyzed in molecular genetic obesity research. Decreased MC4R activity leads to obesity. Currently 166 nonsynonymous, nonsense, deletion, and frameshift MC4R mutations have been described. Vast numbers of these mutations were identified in (extremely) obese individuals. Total or partial loss of MC4R function results from most detected mutations, as shown by in vitro analyses. The heterozygote frequency for these mutations in (extremely) obese individuals cumulates to approximately 2-5%. Surprisingly, two polymorphisms in the MC4R are associated with a slight protection from obesity. Large study groups were screened to be able to pinpoint these rather small effects on body weight. Recently, the advent of genome-wide association studies led to the discovery of association of polymorphisms in the 3' region of the MC4R with obesity. The functional implication of the finding is still unresolved; an effect on gene expression is the most likely mechanism. Synthetic association could not be detected for the MC4R region.