Antiobesity therapeutics with complementary dual‐agonist activities at glucagon and glucagon‐like peptide 1 receptors. Issue 1 (24th September 2021)

• Record Type: Journal Article
• 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
• Is Part Of: Diabetes, obesity & metabolism. Volume 24:Issue 1(2022)
• Page Start: 50
• Page End: 60
• Publication Date: 2021-09-24
• Subjects: GLP‐1 analogue -- glucagon -- weight control -- energy regulation -- glycaemic control -- lipid‐lowering therapy; Diabetes -- Periodicals; Obesity -- Periodicals; Metabolism -- Disorders -- Periodicals; Clinical pharmacology -- Periodicals; 616.462
• DOI: 10.1111/dom.14546
• Languages: English
• ISSNs: 1462-8902

Abstract

Abstract: 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.