Antiobesity therapeutics with complementary dual‐agonist activities at glucagon and glucagon‐like peptide 1 receptors

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2022-01, Vol.24 (1), p.50-60
• Main Authors: Park, Bong Gyu, Kim, Gyeong Min, Lee, Hye‐Jin, Ryu, Jae Ha, Kim, Dong‐Hoon, Seong, Jae‐Young, Kim, Soojeong, Park, Zee‐Yong, Kim, Young‐Joon, Lee, Jaemin, Kim, Jae Il
• Format: Article
• Language: English
• Subjects: Adipose tissue (brown); Agonists; Animals; Antidiabetics; Antifungal agents; Body fat; Body weight loss; Diabetes; Diabetes mellitus; energy regulation; Fatty liver; GLP‐1 analogue; Glucagon; Glucagon - physiology; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor - agonists; glycaemic control; Humans; Insulin; Insulin resistance; Kinases; lipid‐lowering therapy; Lipogenesis; Lipolysis; Lysine; Metabolic disorders; Metabolism; Mice; Obesity; Oxidative stress; Palmitic acid; Peptides; Protein kinase; Receptors, Glucagon - metabolism; Signal transduction; Skeletal muscle; Steatosis; Thermogenesis; weight control
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.14546

Aim To develop more effective and long‐lasting antiobesity and antidiabetic therapeutics by employing novel chemical modifications of glucagon‐like peptide‐1 receptor (GLP‐1R) agonists. Methods We constructed novel unimolecular dual agonists of GLP‐1R and glucagon receptor prepared by linking sEx‐4 and native glucagon (GCG) via lysine or triazole [sEx4‐GCG(K) and sEx4‐GCG(T), respectively] and evaluated their antiobesity and antidiabetic efficacy in the diabetic and obese mouse model. Results Both sEx4‐GCG(K) and sEx4‐GCG(T) showed the beneficial metabolic effects of GLP‐1 and glucagon: they promoted weight loss and ameliorated insulin resistance and hepatic steatosis. They also increased thermogenesis in brown adipose tissue, and lipolysis and β‐oxidation in white adipose tissue, with concomitant suppression of lipogenesis. Furthermore, both dual agonists activated the 5′‐AMP‐activated protein kinase signalling pathway and prevented palmitate‐induced oxidative stress in skeletal muscle cells. Conclusion Through their complementary dual agonism, sEx4‐GCG(T) and sEx4‐GCG(K) induce more marked weight loss and metabolic improvements than conventional agonists, and could be developed as novel therapeutic agents for the treatment of obesity and associated metabolic disorders in humans.