DA-1726 is a novel balanced long-acting oxyntomodulin (OXM) analogue, which is under preclinical development for the treatment of obesity. In this study, the pharmacological effects of DA-1726 were evaluated. DA-1726 exhibited a balanced dual action on GLP-1 receptor (GLP1R) and glucagon receptor (GCGR) in CHO-K1 cells transiently overexpressing each human receptor. In high-fat diet-induced obese mice, 3-week treatment of DA-1726 showed more body weight loss (BWL) and increasing energy expenditure than a pair-fed group. This means that the BWL effect of DA-1726 is due to decreased food intake and increased energy metabolism through GLP1R and GCGR action. In comparison with a GLP1R agonist, DA-1726 showed superior BWL, despite eating more food compared to semaglutide (SEMA) after 4-week treatment in obese mice. At the end of the study, DA-1726 significantly increased the expression of thermogenic genes (Ucp-1 and Ppargc1a) in white adipose tissue (WAT) , and increased WAT browning was histologically confirmed. In addition, DA-1726 inhibited adipocyte differentiation in vitro. Taken together, it suggests that the GCGR action of DA-1726 contributes to reduced adiposity by enhancing fat burning and inhibiting adipogenesis. OXM analogue biased to GCGR fails to control blood glucose despite GLP1R agonism. As a balanced analogue, DA-1726 effectively reduced postprandial glucose excursion in acute oral glucose tolerance test in normal mice. Notably, DA-1726 showed similar glycemic control and excellent BWL to SEMA in hyperglycemic and obese FATZO mice after 4-week treatment. Simultaneously, DA-1726 enhanced insulin sensitivity by significantly reducing fasting plasma insulin and glucose levels. Meanwhile, DA-1726 showed no hypoglycemia risk in overnight fasted normal mice unlike SEMA after a single injection, regardless of dose escalation. Our findings suggest that DA-1726 is a balanced GLP1R/GCGR dual agonist that effectively reduces body weight and blood glucose levels.
T.Kim: None. I.Jung: None. K.Kim: None. B.Lee: None. M.Kim: None. Y.Chae: None.