Abstract：
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.
摘要：
Tirzepatide,葡萄糖依赖性促胰岛素多肽/胰高血糖素样肽1受体（GIPR/GLP-1R）激动剂，has,在临床试验中，表现出更大的葡萄糖减少，体重,与2型糖尿病患者（T2D）的选择性GLP-1R激动剂相比，甘油三酯水平。然而,GIPR激动可能有助于这些疗效改善的细胞机制尚未完全确定.使用人类脂肪细胞和小鼠模型，我们研究了长效GIPR激动剂如何调节禁食和进食脂肪细胞功能.在功能测定中，GIPR激动增强胰岛素信号,增强葡萄糖摄取，并以与胰岛素合作的方式增加葡萄糖向甘油的转化；然而，在没有胰岛素的情况下，GIPR激动剂增加脂解。在用长效GIPR激动剂治疗的饮食诱导的肥胖小鼠中，循环甘油三酯水平在口服脂质攻击期间降低，脂蛋白来源的脂肪酸在脂肪组织中的摄取增加。我们的发现支持长效GIPR激动剂通过与胰岛素合作以增加进食状态下的葡萄糖和脂质清除，同时在禁食状态下胰岛素水平降低时增强脂质释放，从而不同地调节禁食和进食脂肪组织功能的模型。
