Seattle Children's Research Institute, 1900 Ninth Ave, Seattle WA 98101, USA.
Syracuse University, Department of Chemistry, 111 College Place, Syracuse, NY 13244, USA; Alltrna, Cambridge, MA, USA.
Clin Nutr. 2024 Jul;43(7):1782-1790. doi: 10.1016/j.clnu.2024.05.035. Epub 2024 May 28.
While therapies based on endogenous gut peptides such as glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) have been compelling therapeutic agents for obesity and type 2 diabetes (T2D), only a few have achieved long-term weight loss and all have shown significant side-effects, including nausea/malaise and gastrointestinal ailments.
As the pathophysiology of obesity is driven by dysregulation of multiple, inter-related, pathways, we tested a novel peptide targeting multiple receptors of complementary neurocircuits regulating the controls of energy balance.
Response to daily injections of GEP44, a GLP-1R and neuropeptide Y1R and Y2R receptor (Y1R/Y2R) triple agonist was tested vs. the GLP-1R agonist liraglutide (LIRA) in diet-induced obese (DIO) male and female rats. Glucose tolerance tests after intraperitoneal injection of glucose (IPGTT) were performed at baseline and after 14-d of treatment in GEP44 treated rats. Other metabolic parameters were assessed in blood at the end of a 28-d intervention.
Upon conclusion at 28-d, body weight reduction compared to vehicle was -15.6%/-11.9% in response to GEP44, vs. -9.7%/-5.1% after LIRA, males, and females, respectively. Significant reductions of cumulative food intake occurred over 28-d in female rats treated with GEP44 (-30%; p < 0.0001), vs. LIRA (-10%), and in male rats GEP44 (-39%; p < 0.0001), vs. LIRA (-20%; p = 0.003). In IPGTTs, a similar stimulation glucose induced insulin secretion was noted in rats treated with GEP44 and LIRA.
The strong reductions of body weight in response to long-term applications of the triple agonist GEP44 confirms the therapeutic potential of targeting multiple receptors for achieving more robust and potentially more sustained improvement of energy balance.
基于内源性肠道肽（如胰高血糖素样肽-1（GLP-1）受体激动剂（GLP-1RA））的治疗方法已成为肥胖和 2 型糖尿病（T2D）的有效治疗药物，但只有少数药物能实现长期减肥，且所有药物都表现出明显的副作用，包括恶心/不适和胃肠道疾病。
由于肥胖的病理生理学是由多个相互关联的途径失调驱动的，我们测试了一种新型肽，该肽针对调节能量平衡的神经回路的多个互补受体。
在饮食诱导肥胖（DIO）雄性和雌性大鼠中，测试了 GLP-1R 和神经肽 Y1R 和 Y2R 受体（Y1R/Y2R）三重激动剂 GEP44 每日注射的反应，与 GLP-1R 激动剂利拉鲁肽（LIRA）进行了对比。在 GEP44 治疗大鼠中，在接受葡萄糖腹膜内注射（IPGTT）前后进行了基础葡萄糖耐量试验。在 28 天干预结束时，在血液中评估了其他代谢参数。
在 28 天结束时，与载体相比，GEP44 使雄性和雌性大鼠体重分别减轻了-15.6%/-11.9%，而 LIRA 则分别减轻了-9.7%/-5.1%。在雌性大鼠中，经过 28 天的治疗，GEP44 显著减少了累积食物摄入量（-30%；p<0.0001），而 LIRA 则减少了 10%，在雄性大鼠中，GEP44 减少了 39%（p<0.0001），而 LIRA 减少了 20%（p=0.003）。在 IPGTT 中，在接受 GEP44 和 LIRA 治疗的大鼠中，观察到类似的刺激葡萄糖诱导胰岛素分泌。
长期应用三重激动剂 GEP44 可显著降低体重，证实了针对多个受体的治疗潜力，以实现更强大且潜在更持久的能量平衡改善。
