Journal of the Endocrine Society | Effect of ActR2 Antibody on Obesity Phenotype in MC3R-Deficient Mice

This study systematically evaluates the effects of CDD866 on lean body mass and fat distribution in MC3R-deficient mice, revealing its limited efficacy in improving body composition and offering novel insights for obesity-related receptor research.

 

Literature Overview
This study, titled 'Effect Of CDD866, An Anti-activin Type II Receptor Antibody, On The Melanocortin 3 Receptor (MC3R) Deficiency Obesity Phenotype', published in the Journal of the Endocrine Society, reviews the role of MC3R in energy homeostasis and investigates the impact of ActR2-blocking antibody CDD866 on body composition and glucose homeostasis in MC3R-deficient mice. The research highlights that while MC3R-deficient mice exhibit increased adiposity and reduced lean mass, CDD866 treatment shows limited benefits in ameliorating these parameters.

Background Knowledge
MC3R, a member of the melanocortin receptor family, plays a critical role in regulating energy metabolism. MC3R knockout mice are widely used as models for studying obesity and metabolic disorders. ActR2 serves as a shared receptor for myostatin and activin, and blocking antibodies like Bimagrumab have been shown to increase lean mass, though their effects on metabolic functions in MC3R-deficient mice remain unclear. This study employs MC3R-deficient mouse models and ActR2-blocking antibody CDD866 to explore potential interactions between MC3R and ActR2 signaling pathways in body composition regulation.

 

 

Research Methods and Experiments
The study utilized MC3R wild-type (MC3R+/+) and knockout (MC3R-/-) mice, divided into IgG1 control and CDD866 treatment groups. CDD866 was administered via weekly intraperitoneal injections (20 mg/kg) over four weeks. Experimental assessments included weight monitoring, DEXA scans, and glucose/insulin tolerance tests to evaluate therapeutic impacts on body composition and metabolic functions.

Key Conclusions and Perspectives

• CDD866 treatment significantly increased lean mass in all genotypes but did not improve adiposity ratios.
• MC3R-deficient mice exhibited accelerated weight gain after CDD866 administration, with no reduction in fat mass or improvement in glucose/insulin tolerance.
• Findings suggest that the ActR2 signaling pathway is not a primary regulator of the MC3R-deficient obesity phenotype, indicating MC3R may modulate body composition through ActR2-independent mechanisms.
• No significant sex differences were observed, although CDD866-induced weight gain was most pronounced in MC3R+/+ female mice.

Research Significance and Prospects
This work demonstrates that ActR2 blockade fails to correct metabolic dysregulation caused by MC3R deficiency, emphasizing the need to focus on MC3R downstream pathways and their interactions with other receptors in future studies. Additionally, the research provides a molecular evaluation framework for targeted obesity therapies.

 

 

Conclusion
The study reveals that CDD866 primarily enhances lean mass without improving adiposity or metabolic stability in MC3R-deficient mice. These results suggest distinct regulatory roles for MC3R and ActR2 signaling in body composition control, offering critical directions for future obesity-related receptor research. The findings advance understanding of complex energy homeostasis mechanisms and provide reference for developing targeted therapeutic strategies.

 

Eliza A Jansujwicz, Tushar P Patel, Diana M Elizondo, Benjamin T Cole, and Jack A Yanovski. MON-724 Effect Of CDD866, An Anti-activin Type II Receptor Antibody, On The Melanocortin 3 Receptor (MC3R) Deficiency Obesity Phenotype. Journal of the Endocrine Society.