Obesity is considered as a main risk factor for metabolic syndrome. Although there are several anti-obesity drugs, their main mode of action (MoA) is appetite suppression. Thus, body weight loss (BWL) efficacy is limited with benefits fading when the drugs stopped. Glucagon (GCG) has been used to treat hypoglycemia. Recent studies indicated a stimulatory effect of GCG on energy expenditure, suggesting its utilization as an anti-obese drug. Since BWL is a key for insulin resistance (IR) reversal and blood glucose (BG) normalization, we hypothesized that sustained GCG treatment may reduce hyperglycemic risk via IR improvement following efficient BWL. To investigate this hypothesis, we developed a novel long-acting GCG analog, HM15136, and evaluated the effect of HM15136 on BW and BG in vivo. In obese animals, HM15136 demonstrated dose-dependent BWL (-21 ∼ -53% vs. Veh. for DIO mice, -10 ∼ -64% vs. Veh. for DIO rats). Of note, despite an initial increase, BG level rapidly normalized. As to the responsible MoA, a reduced blood lipid and HOMA-IR were observed. In vitro studies demonstrated the increased FGF-21 and adiponectin expression by HM15136 in 3T3-L1 adipocytes. These results suggest that HM15136 could improve insulin sensitivity via multiple mechanisms, leading to normal BG maintenance under chronic GCG receptor stimulation. To further investigate the therapeutic potential of HM15136, BWL efficacy was compared to liraglutide: Greater BWL was observed with HM15136 (-34% and -21% vs. Veh. for HM15136 and liraglutide, respectively). Indirect calorimetry demonstrated enhanced energy expenditure by HM15136. Most interestingly, efficient BWL achieved by HM15136 was maintained during 4 weeks drug-holiday, compared to liraglutide.
In conclusion, our results demonstrate the potential for prolonged GCG receptor stimulation with agent like HM15136 as a novel therapeutic option for obesity treatment. Human studies are needed to confirm these findings and to evaluate the potential safety of HM15136.
J. Kim: None. J. Kim: None. S. Lee: None. J. Lee: None. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd.