Preadipocytes are crucial for healthy adipose tissue expansion. Preadipocyte differentiation is altered in obese individuals, which has been proposed to contribute to obesity-associated metabolic disturbances. Here, we demonstrate that impaired alternative splicing and dysregulated endoplasmic reticulum (ER)- associated protein degradation (ERAD) represent marker pathways of dysfunctional preadipocytes in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). Down-regulation of a key member of the major spliceosome, PRFP8/PRP8, as observed in IR/T2D preadipocytes from subcutaneous (SC) fat, prevented adipogenesis by altering both the expression and splicing patterns of adipogenic transcription factors and lipid droplet-related proteins, while adipocyte differentiation was restored upon recovery of PRFP8/PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of ERAD hyperactivation, as occurs in SC and omental (OM) preadipocytes in IR/T2D obesity. Thus, targeting mRNA splicing and ER proteostasis in preadipocytes could improve adipose tissue function and thus contribute to metabolic health in obese individuals.

中文翻译：

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肥胖相关代谢疾病中前脂肪细胞中 mRNA 剪接和蛋白质稳态受损

前脂肪细胞对于健康的脂肪组织扩张至关重要。肥胖个体的前脂肪细胞分化发生了改变，这被认为是导致肥胖相关代谢紊乱的原因。在这里，我们证明了受损的可变剪接和失调的内质网 (ER) 相关蛋白降解 (ERAD) 代表了患有胰岛素抵抗 (IR)/2 型糖尿病 (T2D) 的肥胖个体功能失调的前脂肪细胞的标志物通路。主要剪接体的关键成员PRFP8 的下调/PRP8，如在来自皮下 (SC) 脂肪的 IR/T2D 前脂肪细胞中所观察到的那样，通过改变脂肪生成转录因子和脂滴相关蛋白的表达和剪接模式来阻止脂肪生成，而脂肪细胞分化在PRFP8 /PRP8恢复正常后恢复水平。在 ERAD 过度活化的条件下，脂肪细胞分化也受到损害，如 IR/T2D 肥胖中的 SC 和网膜 (OM) 前脂肪细胞。因此，靶向前脂肪细胞中的 mRNA 剪接和内质网蛋白稳态可以改善脂肪组织功能，从而有助于肥胖个体的代谢健康。