Antiobesity therapeutics with complementary dual-agonist activities at glucagon and glucagon-like peptide 1 receptors
- 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
- Issue Date
- Jan-2022
- Publisher
- WILEY
- Keywords
- GLP-1 analogue; glucagon; weight control; energy regulation; glycaemic control; lipid-lowering therapy
- Citation
- DIABETES OBESITY & METABOLISM, v.24, no.1, pp.50 - 60
- Indexed
- SCIE
SCOPUS
- Journal Title
- DIABETES OBESITY & METABOLISM
- Volume
- 24
- Number
- 1
- Start Page
- 50
- End Page
- 60
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/143906
- DOI
- 10.1111/dom.14546
- ISSN
- 1462-8902
- 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 beta-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.
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Collections - Graduate School > Department of Biomedical Sciences > 1. Journal Articles
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