Abstract：
BACKGROUND: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：虽然基于内源性肠肽如胰高血糖素样肽-1（GLP-1）受体激动剂（GLP-1RAs）的治疗已经成为肥胖和2型糖尿病（T2D）的治疗药物，只有少数人实现了长期减肥，并且都表现出明显的副作用，包括恶心/不适和胃肠道疾病。
目的：由于肥胖的病理生理学是由多种疾病失调驱动的，相互关联，通路,我们测试了一种新的肽，该肽靶向调节能量平衡的互补神经回路的多个受体。
方法：对每日注射GEP44，GLP-1R和神经肽Y1R和Y2R受体（Y1R/Y2R）三联激动剂的反应进行了比较。GLP-1R激动剂利拉鲁肽（LIRA）在饮食诱导的肥胖（DIO）雄性和雌性大鼠中的应用。在基线和在GEP44处理的大鼠中处理14天之后,在腹膜内注射葡萄糖(IPGTT)之后进行葡萄糖耐量测试。在28天干预结束时评估血液中的其他代谢参数。
结果：在第28天结束时，响应GEP44，与车辆相比，体重减轻为-15.6%/-11.9%，与LIRA后-9.7%/-5.1%，男性,和女性，分别。在用GEP44治疗的雌性大鼠中，累积食物摄入量在28-d内显着减少（-30％；p<0.0001），vs.LIRA（-10%），在雄性大鼠GEP44（-39％；p<0.0001）中，vs.LIRA(-20%;p=0.003)。在IPGTT中，在用GEP44和LIRA治疗的大鼠中观察到类似的刺激葡萄糖诱导的胰岛素分泌.
结论：长期应用三激动剂GEP44后体重的显著降低证实了靶向多种受体的治疗潜力，可实现更稳健和潜在更持续的能量平衡改善。
目的：由于肥胖的病理生理学是由多种疾病失调驱动的，相互关联，通路,我们测试了一种新的肽，该肽靶向调节能量平衡的互补神经回路的多个受体。
方法：对每日注射GEP44，GLP-1R和神经肽Y1R和Y2R受体（Y1R/Y2R）三联激动剂的反应进行了比较。GLP-1R激动剂利拉鲁肽（LIRA）在饮食诱导的肥胖（DIO）雄性和雌性大鼠中的应用。在基线和在GEP44处理的大鼠中处理14天之后,在腹膜内注射葡萄糖(IPGTT)之后进行葡萄糖耐量测试。在28天干预结束时评估血液中的其他代谢参数。
结果：在第28天结束时，响应GEP44，与车辆相比，体重减轻为-15.6%/-11.9%，与LIRA后-9.7%/-5.1%，男性,和女性，分别。在用GEP44治疗的雌性大鼠中，累积食物摄入量在28-d内显着减少（-30％；p<0.0001），vs.LIRA（-10%），在雄性大鼠GEP44（-39％；p<0.0001）中，vs.LIRA(-20%;p=0.003)。在IPGTT中，在用GEP44和LIRA治疗的大鼠中观察到类似的刺激葡萄糖诱导的胰岛素分泌.
结论：长期应用三激动剂GEP44后体重的显著降低证实了靶向多种受体的治疗潜力，可实现更稳健和潜在更持续的能量平衡改善。
