Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell–derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell–derived adipocytes.

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人类干细胞来源的脂肪细胞生理胰岛素抵抗模型的开发


脂肪细胞是人体新陈代谢的关键调节因子，其胰岛素信号传导功能障碍是包括 II 型糖尿病 (T2D) 在内的代谢疾病的核心。然而，人们对胰岛素抵抗发展为 T2D 的过程仍知之甚少。这种有限的理解部分是由于缺乏合适的人类脂肪细胞胰岛素信号传导模型。传统上，脂肪细胞模型无法重现体内胰岛素信号传导，可能是由于暴露于超生理营养和激素条件所致。我们为人类多能干细胞衍生的脂肪细胞开发了一种方案，该方案利用生理营养条件产生与体内脂肪细胞相当的有效胰岛素反应。经过系统优化后，该方案可实现强大的胰岛素刺激葡萄糖摄取和转录胰岛素反应。此外，致敏的脂肪细胞暴露于生理性高胰岛素血症会抑制胰岛素刺激的葡萄糖摄取并失调胰岛素反应性转录。总的来说，我们的方法为使用人类多能干细胞来源的脂肪细胞进行胰岛素信号传导和抵抗的机制研究提供了一个新的平台。