Melanocortin-4 receptor: A novel signalling pathway involved in body weight regulation

For many years, genetically obese mouse strains have provided models for hu man obesity. The A(vy)/-agouti mouse, one of the oldest obese mouse models, is characterized by maturity-onset obesity and diabetes as a result of ect opic expression of the secreted protein hormone, agouti protein. Agouti pro tein is normally expressed in hair follicles to regulate pigmentation throu gh antagonism of the melanocortin-1 receptor, but in-vitro studies have dem onstrated that the hormone also has potent antagonist activity for the mela nocortin-4 receptor (MC4-R). Subsequent development of the MC4-R knockout m ouse model demonstrated that MC4-R plays a role in weight homeostasis as th ese mice recapitulated the metabolic defects of the agouti mouse. Further e vidence for this hypothesis was obtained from pharmacological studies utili zing peptides with MC4-R agonist activity, that inhibitied food intake (whe n administered intracerebrarly), Additional studies with peptide antagonist s have now implicated the MC4-R in the leptin signalling pathway. Finally, evidence that the MCC-R may play a role in human obesity has been obtained from the identification of a dis-functional variant of the receptor in gene tically obese subjects.