Introduction and Objective: Obesity has reached epidemic proportions globally, posing a critical public health crisis. To address this, HM15275, a novel long-acting GLP-1/GIP/Glucagon triple agonist was developed, demonstrating potent weight loss and glycemic control in prior preclinical studies. The present study further investigates the effects of HM15275 on body weight and body composition over an extended period and its underlying mechanisms.Methods: The effect of HM15275 on body weight and body composition were assessed in DIO mice. To investigate the weight loss mechanism of HM15275, pair-fed and energy balance studies were conducted, and mesenteric white adipose tissue (mWAT) was subjected to immunohistochemistry. Tirzepatide (TZP) and retatrutide (RETA, in-house synthesis) served as comparative controls.Results: In DIO mice, HM15275 treatment for 3 weeks resulted in a greater weight loss (-39.9% vs. D0) than TZP (-25.3% vs. D0). Switching from TZP to HM15275 at week 2 led to further weight loss. Mechanistically, a pair-fed study revealed that HM15275 induced both food intake-dependent and -independent weight loss in which, latter was driven by increased energy expenditure. HM15275 also enhanced expression of PGC-1α and UCP-1 in mWAT, being more pronounced than TZP, which indicates stronger fat browning effect. Furthermore, longer treatment of HM15275 for 6 weeks significantly reduced more body weight than RETA. Notably, greater fat mass reduction and no difference in lean mass by HM15275 contributed to more improved weight loss quality compared to RETA.Conclusion: In conclusion, HM15275 demonstrates potent weight loss with improved weight loss quality in DIO mice. Also, comprehensive elucidation of the underlying mechanism of action has been demonstrated. Clinical translation of such findings is under investigation in an ongoing phase 1, 4-week multiple ascending dose (MAD) study in obese patients.
S. Park: None. Y. Kim: None. J. Kim: None. S. Lee: None. E. Park: None. D. Lee: None. J.A. Kim: None. S. Hong: None. S. Bae: None. S. Lee: None. I. Choi: None.
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