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

Oct 15, 2025Metabolism: clinical and experimental

A drug activating two key receptors for treating diabetes and obesity

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Abstract

Reductions in calorie intake and body weight were similar across groups treated with the novel peptide KCEM1 and standard therapies semaglutide and tirzepatide.

KCEM1 is a polypharmacy approach combining GLP-1 and melanocortin receptor agonism in a single peptide.
Similar reductions in body weight and calorie intake were observed in rats treated with KCEM1, semaglutide, and tirzepatide over 7 weeks.
KCEM1 provided superior glycemic control during glucose tolerance testing compared to the other treatments.
Gene expression analyses showed that KCEM1 significantly increased glucose transporter 4 (GLUT4) and Pgk1 in skeletal muscle.
KCEM1 also reduced inflammatory markers IL-6 and TNF-α in liver tissue and lowered hepatic lipid content.
Improvement in metabolic dysfunction-associated steatohepatitis (MASH) scoring was noted with KCEM1 treatment.

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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.

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

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