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.
Bibliographical noteFunding Information:
Gwangju Institute of Science and Technology; National Research Foundation of Korea, Grant/Award Numbers: NRF‐2015M3A9E7029172, NRF‐2019R1A4A1029724 Funding information
This research was supported by the Basic Science Research Program, through the National Research Foundation (NRF) of Korea, funded by the Ministry of Science and ICT (NRF‐2015M3A9E7029172 and NRF‐2019R1A4A1029724), and by the GIST Research Institute grant.
© 2021 John Wiley & Sons Ltd.
- GLP-1 analogue
- energy regulation
- glycaemic control
- lipid-lowering therapy
- weight control
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism