Melanocortin-4 receptor: a novel signalling pathway involved in body weight regulation.
For many years, genetically obese mouse strains have provided models for human obesity. The Avy/-agouti mouse, one of the oldest obese mouse models, is characterized by maturity-onset obesity and diabetes as a result of ectopic expression of the secreted protein hormone, agouti protein. Agouti protein is normally expressed in hair follicles to regulate pigmentation through antagonism of the melanocortin-1 receptor, but in-vitro studies have demonstrated that the hormone also has potent antagonist activity for the melanocortin-4 receptor (MC4-R). Subsequent development of the MC4-R knockout mouse model demonstrated that MC4-R plays a role in weight homeostasis as these mice recapitulated the metabolic defects of the agouti mouse. Further evidence for this hypothesis was obtained from pharmacological studies utilizing peptides with MC4-R agonist activity, that inhibited food intake (when administered intracerebrally). Additional studies with peptide antagonists have now implicated the MC4-R in the leptin signalling pathway. Finally, evidence that the MC4-R may play a role in human obesity has been obtained from the identification of a dis-functional variant of the receptor in genetically obese subjects.
Fisher
S L
SL
Department of Metabolic Diseases, Hoffmann LaRoche, Nutley, NJ 07110, USA.
Yagaloff
K A
KA
Burn
P
P
D000818:Animals; D001835:Body Weight; D006801:Humans; D020738:Leptin; D051379:Mice; D008815:Mice, Inbred Strains; D008954:Models, Biological; D009765:Obesity / Q000503:physiopathology; D010641:Phenotype; D011506:Proteins / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000502:physiology*; D015398:Signal Transduction
D020738:Leptin; D011506:Proteins; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide