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Melanocortin-4 receptor: a novel signalling pathway involved in body weight regulation
S L Fisher1, K A Yagaloff, P Burn
1Department of Metabolic Diseases, Hoffmann LaRoche, Nutley, NJ 07110, USA.
Abstract:
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.
Insights
Genetically obese mice reveal the melanocortin-4 receptor (MC4-R) is crucial for weight control. Blocking MC4-R activity can lead to obesity and diabetes, highlighting its role in human weight regulation.
Area of Science:
- Endocrinology
- Genetics
- Neuroscience
Background:
- Genetically obese mouse models have long been used to study human obesity.
- The Avy/-agouti mouse exhibits obesity and diabetes due to ectopic agouti protein expression.
- Agouti protein antagonizes melanocortin-1 receptor (MC1-R) for pigmentation and melanocortin-4 receptor (MC4-R) in vitro.
Purpose of the Study:
- To investigate the role of melanocortin-4 receptor (MC4-R) in weight homeostasis.
- To explore the connection between MC4-R and the leptin signaling pathway.
- To assess the potential involvement of MC4-R dysfunction in human obesity.
Main Methods:
- Utilized MC4-R knockout mouse models to study metabolic defects.
- Conducted pharmacological studies with MC4-R agonists and antagonists.
- Identified MC4-R variants in genetically obese human subjects.
Main Results:
- MC4-R knockout mice exhibited metabolic defects similar to agouti mice.
- MC4-R agonists administered intracerebrally inhibited food intake.
- MC4-R antagonists implicated the receptor in the leptin signaling pathway.
- A dis-functional MC4-R variant was found in obese individuals.
Conclusions:
- MC4-R plays a significant role in regulating body weight homeostasis.
- The MC4-R is implicated in both central appetite control and the leptin signaling pathway.
- MC4-R dysfunction is a potential factor contributing to human obesity.