Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents
Synergistic metabolic benefits of an exenatide analogue and cholecystokinin in diet-induced obese and leptin-deficient rodents
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DOI：
10.1111/dom.12390
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发表时间：
2015-01-01
影响因子：
5.8
通讯作者：
Roth, J. D.
中科院分区：
文献类型：
--
作者：
Trevaskis, J. L.;Sun, C.;Roth, J. D.
目的：测试胆囊收缩素（CCK）加胰淀素或胰高血糖素样肽-1受体（GLP-1 R）激动剂对饮食诱导肥胖（DIO）啮齿动物代谢变量的影响。CCK-8的稳定乙酰化版本（Ac-Y*-CCK-8），选择性CCK 1受体（CCK 1 R）或CCK 2受体（CCK 2 R）激动剂，胰淀素或GLP-1 R激动剂和艾塞那肽类似物AC 3174以选择的组合通过连续皮下输注给予DIO大鼠14天，或给予Lepob/Lepob小鼠28天，并评估代谢变量。Ac-Y*-CCK-8与胰淀素或AC 3174联合给药可诱导DIO大鼠体重减轻超过相加，AC 3174 + Ac-Y*-CCK-8治疗的总体效果更大。AC 3174与特异性CCK 1 R激动剂（而非CCK 2 R激动剂）的共输注重现了DIO大鼠中AC 3174 + Ac-Y*-CCK-8介导的体重减轻，表明协同作用由CCK 1 R激活介导。在DIO大鼠中进行的4x 4全因子响应面方法学研究中，观察到AC 3174和CCK 1 R选择性激动剂对体重和摄食量的协同相互作用。AC 3174和CCK 1 R选择性激动剂的肥胖糖尿病Lepob/Lepob小鼠的共同管理引起了显着更大的减少糖化血红蛋白和食物摄入量的百分比相对于单一药物治疗groups.Conclusions的总和影响：联合GLP-1 R和CCK 1 R激动的抗肥胖和抗糖尿病的潜力是一种值得进一步研究的方法。
Aim: To test the impact of cholecystokinin (CCK) plus either amylin or a glucagon-like peptide-1 receptor (GLP-1R) agonist on metabolic variables in diet-induced obese (DIO) rodents.Methods: A stabilized acetylated version of CCK-8 (Ac-Y*-CCK-8), selective CCK1 receptor (CCK1R) or CCK2 receptor (CCK2R) agonists, amylin or the GLP-1R agonist and exenatide analogue AC3174 were administered in select combinations via continuous subcutaneous infusion to DIO rats for 14 days, or Lepob/Lepob mice for 28 days, and metabolic variables were assessed.Results: Combined administration of Ac-Y*-CCK-8 with either amylin or AC3174 induced greater than additive weight loss in DIO rats, with the overall magnitude of effect being greater with AC3174+ Ac-Y*-CCK-8 treatment. Co-infusion of AC3174 with a specific CCK1R agonist, but not a CCK2R agonist, recapitulated the weight loss mediated by AC3174+ Ac-Y*-CCK-8 in DIO rats, suggesting that synergy is mediated by CCK1R activation. In a 4x 4 full-factorial response surface methodology study in DIO rats, a synergistic interaction between AC3174 and the CCK1R-selective agonist on body weight and food intake was noted. Co-administration of AC3174 and the CCK1R-selective agonist to obese diabetic Lepob/Lepob mice elicited a significantly greater reduction in percentage of glycated haemoglobin and food intake relative to the sum effects of monotherapy groups.Conclusions: The anti-obesity and antidiabetic potential of combined GLP-1R and CCK1R agonism is an approach that warrants further investigation.