Mutations in melanocortin-4 receptor and human obesity.

Multiple lines of investigations demonstrated that the melanocortin-4 receptor (MC4R) is a critical regulator of energy homeostasis from fishes to humans. Clinical studies in humans showed that mutations in the MC4R gene are the most prevalent form of monogenic obesity. More than 150 mutations have been identified from subjects of different ethnic backgrounds. Functional analyses of the mutant MC4Rs revealed multiple defects, including cell-surface expression, ligand binding, and signaling. Based on the defects, the mutants can be classified into five classes. Potential therapeutic implications from the analyses of the naturally occurring MC4R mutations, such as novel ligands and pharmacological chaperones, are highlighted.