1926-P: Potent Weight Loss Mechanism of a Novel Long-Acting Glucagon Analog, HM15136, in Animal Models of Obesity

Abstract

Several studies have demonstrated that glucagon plays an essential role in the regulation of body weight via both increase of energy expenditure and suppression of appetite, suggesting its potential application for obesity management. Consistent with this, we previously observed that chronic treatment of the novel long-acting glucagon analog, HM15136, led to efficient body weight loss (BWL) in diet-induced obesity (DIO) mice. To further investigate the therapeutic benefits of HM15136 in obesity, the present study compared the BWL effect with available GLP-1 agonists and investigated the underlying mechanism for efficient BWL by HM15136. In DIO mice, chronic treatment of HM15136 showed greater BWL (-38.5% vs. vehicle) than GLP-1 agonists such as liraglutide, dulaglutide, and semaglutide (-16.8, -2.5, and -11.0% vs. vehicle). Of note, unlike liraglutide, more BWL was observed even under pair-feeding conditions, indicating the appetite regulation-independent BWL by HM15136. As to the responsible mechanism, HM15136 increased the expression of PGC-1α and UCP-1 in white adipose tissue (WAT), leading to enhanced energy expenditure. Together with the reduced respiratory exchange ratio, these results suggest that HM15136 induce WAT browning through which fat utilization and energy expenditure increases. To explore an additional mechanism for BWL by HM15136, oral lipid tolerance test (oLTT) was performed. Interestingly, blood TG level during oLTT was significantly decreased by HM15136 treatment, which coincided with decreased blood bile acid and ApoB48. These results suggest that the inhibition of lipid absorption is involved, at least in part, in efficient BWL by HM15136. Therefore, HM15136 could be a potential option for the management of obesity via favorable regulation of energy expenditure and lipid absorption in addition to appetite inhibition. Efficacy study in obese patients is ongoing to assess the clinical relevance of these findings. Disclosure J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. J. Lee: Employee; Self; Hanmi Pharmaceutical. S. Lee: Employee; Spouse/Partner; Hanmi Pharmaceutical. S. Bae: Employee; Self; Hanmi Pharmaceutical. D. Kim: Board Member; Self; Hanmi Pharmaceutical. I. Choi: Board Member; Self; Hanmi Pharmaceutical.