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Peer-reviewedCC BY-NC-NDNature Communications

Dual activation of MC3R and MC4R drives weight loss and reduces food intake in male primates with obesity

  • Jillian L. Seiler1
  • Anna Chiara Impastato1
  • E. Zhang1
  • Kade J Kelley1
  • Thomas L. Bennett1
  • Bradley Studnitzer1
  • Claudia R. Prindle1
  • Benjamin H. Rajewski1
  • Barry A. Badeau1
  • Xinjian Jiang2
  • Russell Potterfield1
  • Jordan Y Delev3
1 more authors
  • Daniel L. Marks4
4 affiliations
  1. 1Endevica Bio, Northbrook, IL, USA
  2. 2WuXi Apptec, Shanghai, China
  3. 3Endevica Bio, Northbrook, IL, USA. [email protected]
  4. 4Endevica Bio, Northbrook, IL, USA. [email protected]
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Abstract

Introductory Paragraph The melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists prompted the investigation of whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation is key to unlocking the melanocortin system for the treatment of general obesity. To test this hypothesis, we designed and synthesized novel peptides to probe the distinct and combined roles of MC3R and MC4R in nonhuman primates (NHPs). We show that selectively agonizing MC3R modulates food intake in a state-dependent manner. Moreover, co-agonism of MC3R and MC4R results in more substantial metabolic effects than selective MC4R agonism, highlighting both a non-redundant and a cooperative role of MC3R. To leverage these discoveries, we developed 710GO, an orally-available MC3R/MC4R dual agonist peptide that induces significant weight loss in diet-induced obese (DIO) NHPs. Oral 710GO treatment demonstrates limited weight rebound, has additive effects in combination with GLP-1s, and exhibits a clean safety profile. These results reestablish the melanocortin system, specifically concerted MC3R/MC4R agonism, as a viable mechanism for next-generation obesity therapeutics.

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Cite

BibTeXRIS
BibTeX
@article{seiler2026dual,
  title = {{Dual activation of MC3R and MC4R drives weight loss and reduces food intake in male primates with obesity}},
  author = {Jillian L. Seiler and Anna Chiara Impastato and E. Zhang and Kade J Kelley and Thomas L. Bennett and Bradley Studnitzer and Claudia R. Prindle and Benjamin H. Rajewski and Barry A. Badeau and Xinjian Jiang and Russell Potterfield and Jordan Y Delev and Daniel L. Marks},
  journal = {Nature Communications},
  year = {2026},
  month = may,
  doi = {10.1038/s41467-026-73372-x},
  url = {https://doi.org/10.1038/s41467-026-73372-x},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Dual activation of MC3R and MC4R drives weight loss and reduces food intake in male primates with obesity
AU  - Jillian L. Seiler
AU  - Anna Chiara Impastato
AU  - E. Zhang
AU  - Kade J Kelley
AU  - Thomas L. Bennett
AU  - Bradley Studnitzer
AU  - Claudia R. Prindle
AU  - Benjamin H. Rajewski
AU  - Barry A. Badeau
AU  - Xinjian Jiang
AU  - Russell Potterfield
AU  - Jordan Y Delev
AU  - Daniel L. Marks
PY  - 2026
DA  - 2026/05/29
JO  - Nature Communications
DO  - 10.1038/s41467-026-73372-x
UR  - https://doi.org/10.1038/s41467-026-73372-x
AB  - Introductory Paragraph The melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists prompted the investigation of whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation is key to unlocking the melanocortin system for the treatment of general obesity. To test this hypothesis, we designed and synthesized novel peptides to probe the distinct and combined roles of MC3R and MC4R in nonhuman primates (NHPs). We show that selectively agonizing MC3R modulates food intake in a state-dependent manner. Moreover, co-agonism of MC3R and MC4R results in more substantial metabolic effects than selective MC4R agonism, highlighting both a non-redundant and a cooperative role of MC3R. To leverage these discoveries, we developed 710GO, an orally-available MC3R/MC4R dual agonist peptide that induces significant weight loss in diet-induced obese (DIO) NHPs. Oral 710GO treatment demonstrates limited weight rebound, has additive effects in combination with GLP-1s, and exhibits a clean safety profile. These results reestablish the melanocortin system, specifically concerted MC3R/MC4R agonism, as a viable mechanism for next-generation obesity therapeutics.
SN  - 2041-1723
ER  -