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

Bong Gyu Park, Gyeong Min Kim, Hye Jin Lee, Jae Ha Ryu, Dong Hoon Kim, Jae Young Seong, Soojeong Kim, Zee Yong Park, Young Joon Kim, Jaemin Lee, Jae Il Kim

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)50-60
Number of pages11
JournalDiabetes, Obesity and Metabolism
Volume24
Issue number1
DOIs
Publication statusPublished - 2022 Jan

Keywords

  • GLP-1 analogue
  • energy regulation
  • glucagon
  • glycaemic control
  • lipid-lowering therapy
  • weight control

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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