2. Academic Validation
  3. A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity

A melanocortin 4- and glucagon-like peptide 1 receptor multiple agonist for the treatment of diabetes and obesity

  • Metabolism. 2025 Oct 13:174:156414. doi: 10.1016/j.metabol.2025.156414.
Emily F Ashlaw 1,  Clinton T Elfers 2,  Kylie S Chichura 1,  Isabella Chavez Miranda 1,  Aelish McGivney 1,  Oleg G Chepurny 3,  George G Holz 4,  Ginger Mullins 5,  Laura J den Hartigh 6,  Yongjun Liu 7,  Christian L Roth 8,  Robert P Doyle 9
Affiliations

Affiliations

  • 1 Syracuse University, Department of Chemistry, 111 College Place, Syracuse, NY, 13244, USA.
  • 2 Seattle Children's Research Institute, Seattle, WA, 98195, USA; University of Washington School of Medicine, Department of Pediatrics, Seattle, WA, 98195, USA.
  • 3 State University of New York, Upstate Medical University, Department of Medicine, Syracuse, NY, 13245, USA.
  • 4 State University of New York, Upstate Medical University, Department of Medicine, Syracuse, NY, 13245, USA; State University of New York, Upstate Medical University, Department of Pharmacology, Syracuse, NY, 13245, USA.
  • 5 Seattle Children's Research Institute, Seattle, WA, 98195, USA.
  • 6 University of Washington, Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, UW Medicine Diabetes Institute, Seattle, WA, 98195, USA.
  • 7 University of Washington, Department of Laboratory Medicine and Pathology, Seattle, WA, 98195, USA.
  • 8 Seattle Children's Research Institute, Seattle, WA, 98195, USA; University of Washington School of Medicine, Department of Pediatrics, Seattle, WA, 98195, USA. Electronic address: Christian.roth@seattlechildrens.org.
  • 9 Syracuse University, Department of Chemistry, 111 College Place, Syracuse, NY, 13244, USA; State University of New York, Upstate Medical University, Department of Medicine, Syracuse, NY, 13245, USA; State University of New York, Upstate Medical University, Department of Pharmacology, Syracuse, NY, 13245, USA. Electronic address: rpdoyle@syr.edu.
PMID: 41093057 DOI: 10.1016/j.metabol.2025.156414
Abstract

Obesity and its sequelae cause significant morbidity and mortality worldwide. Current glucagon-like peptide-1 (GLP-1) receptor agonist-based treatments have significant side-effects associated with high rates of treatment discontinuation. Such concerns are greater still in children and adolescents. Thus, there remains a clinical unmet need to develop obesity and/or T2D mellitus therapies with significantly improved tolerability. Herein, we examined a polypharmacy approach combining melanocortin (MC) 4-, and GLP-1-receptor agonism in a single monomeric peptide based on α-MSH and Exendin-4 to bind and stimulate different peptide receptors in vitro, and to drive reductions in body weight and food intake in up to 7 weeks of treatment in comparison to semaglutide and tirzepatide as standard of care positive controls in diet-induced obese rats. Despite the monomeric peptide GLP-1-/MC4-receptor multiple agonist (KCEM1) being a non-lipidated, weaker GLP-1R agonist compared to semaglutide and tirzepatide, reductions in calorie intake and body weight were similar in all three groups after daily subcutaneous injections of the three peptides. In addition, KCEM1 offered superior glycemic control during glucose tolerance testing. In gene expression analyses, KCEM1, but not semaglutide or tirzepatide, significantly increased expression of glucose transporter 4 (GLUT4) and key glycolysis enzyme Pgk1 in skeletal muscle, while it reduced genetic markers of inflammation in different tissues, including inflammatory markers IL-6 and TNF-α in liver tissue. Furthermore, KCEM1 lowered hepatic lipid content and improved metabolic dysfunction-associated steatohepatitis (MASH) scoring. Overall, these data extend emerging concepts around the use of multi-receptor polypharmacy to treat metabolic syndrome.

Keywords

(MC4) receptor; Glucagon-like peptide-1 (GLP-1) receptor; Glucoregulation; Melanocortin; Obesity; Polypharmacy.

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