Department of Cell Biology, Physiology and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC)/University of Córdoba/Reina Sofía University Hospital, Córdoba, Spain.
CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
Elife. 2021 Sep 21;10:e65996. doi: 10.7554/eLife.65996.
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 aimed at identifying the pathogenic processes underlying impaired adipocyte differentiation in obese individuals with insulin resistance (IR)/type 2 diabetes (T2D). We report that down-regulation of a key member of the major spliceosome, /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 /PRP8 normal levels. Adipocyte differentiation was also compromised under conditions of endoplasmic reticulum (ER)-associated protein degradation (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.
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改变，这被认为导致了与肥胖相关的代谢紊乱。在这里，我们旨在确定胰岛素抵抗（IR）/2 型糖尿病（T2D）肥胖个体中脂肪细胞分化受损的致病过程。我们报告说，在来自皮下（SC）脂肪的 IR/T2D 前脂肪细胞中观察到的主要剪接体关键成员 /PRP8 的下调，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，阻止了脂肪生成，而脂肪细胞分化在 /PRP8 正常水平恢复后得到恢复。在 ER 相关蛋白降解（ERAD）过度激活的情况下，脂肪细胞分化也受到损害，就像在 IR/T2D 肥胖的 SC 和网膜（OM）前脂肪细胞中一样。因此，在前脂肪细胞中靶向 mRNA 剪接和 ER 蛋白稳态可能改善脂肪组织功能，从而有助于肥胖个体的代谢健康。
