替西帕肽通过长效激活GIP受体调节脂肪细胞营养代谢，这一成果由美国礼来公司William Roell课题组经过不懈努力而取得。相关论文于2024年6月14日发表在《细胞—代谢》杂志上。

据悉，替西帕肽是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，在2型糖尿病(T2D)患者中，替西帕肽显示出更强的血糖、体重和甘油三酯水平的降低。然而，通过GIPR激动剂可能有助于这些改善的疗效结果的细胞机制尚未完全确定。

使用人类脂肪细胞和小鼠型，该研究组研究了长效葡萄糖依赖性促胰岛素多肽（GIPR）激动剂，如何调节禁食和喂养脂肪细胞的功能。在功能分析中，GIPR激动作用增强胰岛素信号，增加葡萄糖摄取，并以与胰岛素合作的方式增加葡萄糖向甘油的转化；然而，在缺乏胰岛素的情况下，GIPR激动剂增加了脂肪分解。

在使用长效GIPR激动剂治疗的饮食诱导肥胖小鼠中，循环甘油三酯水平在口服脂质刺激期间降低，脂肪组织对脂蛋白源性脂肪酸的摄取增加。他们的发现支持了一个长效GIPR激动剂模型，该模型通过与胰岛素合作，在进食状态下增加葡萄糖和脂质清除，同时在禁食状态下增加胰岛素水平降低时脂质释放，从而调节禁食和喂食脂肪组织功能的差异。

附：英文原文

Title: Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor

Author: 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

Issue&Volume: 2024-06-14

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.

DOI: 10.1016/j.cmet.2024.05.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(24)00186-4