Clinical use of glucagon (GCG) has long been limited to the acute treatment of insulin-induced hypoglycemia. However, recent studies demonstrate that GCG also plays a central role in the regulation of lipid metabolism and body weight, suggesting its potential application in managing obesity. Consistent with this new concept, we observed that chronic treatment with the novel long-acting glucagon analog, HM15136, led to body weight loss (BWL) with minimized effects on blood glucose control (BG). To further explore the therapeutic potential of HM15136 in obesity, the present study compared the BWL effects of HM15136 with various incretin therapeutics targeting obesity, and investigated the potential BWL mechanism in vivo. In DIO mice, HM15136 showed greater BWL effects than GLP-1 agonists such as liraglutide, dulaglutide, and semaglutide. Of note, more BWL was also confirmed even under pair-feeding conditions with liraglutide, indicating appetite-independent BWL by HM15136. As to the postulated mechanism, HM15136 increased the expression of PGC-1α and UCP-1 in white adipose tissue (WAT). Consistent with these results, HM15136 enhanced the energy expenditure in DIO mice. Taken together with the reduced respiratory exchange ratio, these results suggested that HM15136 may induce WAT browning a mechanism through which energy expenditure can increase. We then evaluated a flexible dosing regimen for HM15136, and similar BWL effects were confirmed for human weekly- and monthly-mimetic dosing groups. Most interestingly, BWL achieved by HM15136, but not liraglutide, was maintained after 4 weeks without drug treatment. No abnormal changes in BG and HbA1c were observed. Based on these results, we propose that the novel long-acting glucagon analog, HM15136, could be a potential therapeutic option for the management of obesity. Human studies are needed to confirm these therapeutic benefits and to evaluate the safety of HM15136.
J. Lee: None. J. Kim: None. J. Kim: None. E. Park: None. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: None. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd.