Naturally occurring mutations in G protein-coupled receptors associated with obesity and type 2 diabetes mellitus.

G protein-coupled receptors (GPCRs) are the largest family of membrane receptors involved in the regulation of almost all known physiological processes. Dysfunctions of GPCR-mediated signaling have been shown to cause various diseases. The prevalence of obesity and type 2 diabetes mellitus (T2DM), two strongly associated disorders, is increasing worldwide, with tremendous economical and health burden. New safer and more efficacious drugs are required for successful weight reduction and T2DM treatment. Multiple GPCRs are involved in the regulation of energy and glucose homeostasis. Mutations in these GPCRs contribute to the development and progression of obesity and T2DM. Therefore, these receptors can be therapeutic targets for obesity and T2DM. Indeed some of these receptors, such as melanocortin-4 receptor and glucagon-like peptide 1 receptor, have provided important new drugs for treating obesity and T2DM. This review will focus on the naturally occurring mutations of several GPCRs associated with obesity and T2DM, especially incorporating recent large genomic data and insights from structure-function studies, providing leads for future investigations.