替扎帕肽通过长效激活 GIP 受体调节脂肪细胞的营养代谢。

Cell metabolism Pub Date : 2024-07-02 Epub Date: 2024-06-14 DOI:10.1016/j.cmet.2024.05.010
Ajit Regmi, Eitaro Aihara, Michael E Christe, Gabor Varga, Thomas P Beyer, Xiaoping Ruan, Emily Beebe, Libbey S O'Farrell, Melissa A Bellinger, Aaron K Austin, Yanzhu Lin, Haitao Hu, Debra L Konkol, Samantha Wojnicki, Adrienne K Holland, Jessica L Friedrich, Robert A Brown, Amanda S Estelle, Hannah S Badger, Gabriel S Gaidosh, Sander Kooijman, Patrick C N Rensen, Tamer Coskun, Melissa K Thomas, William Roell
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摘要

替扎帕肽是一种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,在临床试验中,与选择性 GLP-1R 激动剂相比,它对 2 型糖尿病(T2D)患者的血糖、体重和甘油三酯水平的降低幅度更大。然而,GIPR 激动可能有助于改善疗效的细胞机制尚未完全明确。我们利用人类脂肪细胞和小鼠模型,研究了长效 GIPR 激动剂如何调节空腹和进食脂肪细胞的功能。在功能测试中,GIPR 激动剂增强了胰岛素信号传导,增加了葡萄糖摄取,并以与胰岛素合作的方式增加了葡萄糖向甘油的转化;然而,在没有胰岛素的情况下,GIPR 激动剂增加了脂肪分解。用长效 GIPR 激动剂治疗饮食诱导的肥胖小鼠,在口服脂质挑战过程中循环甘油三酯水平降低,脂蛋白衍生脂肪酸摄入脂肪组织的量增加。我们的研究结果支持长效 GIPR 激动剂通过与胰岛素合作,在进食状态下增强葡萄糖和脂质的清除,同时在进食状态下胰岛素水平降低时增强脂质的释放,从而以不同方式调节空腹和进食状态下脂肪组织功能的模型。
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Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

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.

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