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<p>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 has prompted investigation into whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation may more effectively engage this pathway for the treatment of general obesity. Here we show that selective MC3R agonism modulates food intake in a state-dependent manner, and that co-agonism of MC3R and MC4R produces greater metabolic effects than selective MC4R agonism alone, consistent with non-redundant and cooperative roles. Using novel peptides in male nonhuman primates and rodents, we develop 710GO, an orally available MC3R/MC4R dual agonist that induces significant weight loss in primates with diet-induced obesity. Oral 710GO demonstrates limited weight rebound, compatibility with GLP-1–based therapies, and a favorable preclinical safety profile. These findings support combined MC3R/MC4R agonism as a promising approach for next-generation obesity therapeutics.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月29日

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  • Jillian L. Seiler,
  • Anna C. Impastato,
  • Emma Xiaoyu Zhang,
  • Kade J. Kelley,
  • Thomas L. Bennett,
  • Bradley Studnitzer,
  • Claudia R. Prindle,
  • Benjamin H. Rajewski,
  • Barry A. Badeau,
  • Xinjian Jiang,
  • Russell Potterfield,
  • Jordan Y. Delev,
  • Daniel L. Marks

摘要

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 has prompted investigation into whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation may more effectively engage this pathway for the treatment of general obesity. Here we show that selective MC3R agonism modulates food intake in a state-dependent manner, and that co-agonism of MC3R and MC4R produces greater metabolic effects than selective MC4R agonism alone, consistent with non-redundant and cooperative roles. Using novel peptides in male nonhuman primates and rodents, we develop 710GO, an orally available MC3R/MC4R dual agonist that induces significant weight loss in primates with diet-induced obesity. Oral 710GO demonstrates limited weight rebound, compatibility with GLP-1–based therapies, and a favorable preclinical safety profile. These findings support combined MC3R/MC4R agonism as a promising approach for next-generation obesity therapeutics.