Introduction and Objective: Incretin drugs have demonstrated remarkable efficacy in body weight reduction and improving metabolic parameters. However, there may be challenges associated with lean mass loss and long-term health benefits. Urocortin-2 (UCN2) is a corticotropin-releasing factor receptor 2 (CRFR2) agonist and has been known to regulate whole body glucose metabolism, insulin sensitivity and skeletal muscle hypertrophy. In current study, we explore the effects of HM17321, a novel CRFR2 selective UCN2 analog, in combination with HM15275, a GLP-1/GIP/Glucagon triple agonist, on body composition in diet-induced obese (DIO) mice.Methods: DIO mice were subcutaneously injected with vehicle, HM17321 and HM15275 either alone or in combination for 4 weeks. In a second study, DIO mice were initially treated with HM15275 for 3 weeks and then the mice were either continued with HM15275 or switched to HM17321 for an additional 3 weeks. Body weight and food intake were measured during the study, and body composition was determined based on TD-NMR at baseline and after treatment. Skeletal muscle weight and performance were assessed after treatment.Results: HM17321 significantly reduced body weight and fat mass while simultaneously increasing lean mass in DIO mice. Co-administration of HM17321 and HM15275 for 4 weeks led to a greater reduction in body weight and fat mass than either compound alone. Notably, the combination of HM17321 and HM15275 significantly increased skeletal muscle weight and restored muscle function. These effects were observed even with various dose combinations. In line with this, switching to HM17321 maintained fat loss induced by HM15275 while preserving lean mass.Conclusion: The combination of HM17321 and HM15275 resulted in enhanced fat reduction while preserving lean mass, indicating improved body composition during weight loss. These findings suggest that HM17321 could be a promising therapeutic option in combination strategies for treating obesity.
H. Kwon: None. J.A. Kim: None. S. Lee: None. J. Kim: None. S. Lee: None. I. Choi: None.
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