Sánchez-Ceinos, JuliaGuzmán-Ruiz, RocíoRangel-Zúñiga, Oriol AlbertoLópez-Alcalá, JaimeMoreno-Caño, ElenaDel Río-Moreno, MercedesRomero-Cabrera, Juan LuisPérez-Martínez, PabloMaymo-Masip, ElsaVendrell, JoanFernández-Veledo, SoniaFernández-Real, José ManuelLaurencikiene, JurgaRydén, MikaelMembrives, AntonioLuque, Raul MLópez-Miranda, JoséMalagón, María M2025-01-072025-01-072021-09-21https://hdl.handle.net/10668/27857Preadipocytes 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, 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 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/ER-proteostasisERADRNA splicingUPRcell biologyhumanobesity-related metabolic diseasespreadipocytesAdipocytesAdipogenesisAdultCell DifferentiationCell LineDiabetes Mellitus, Type 2FemaleHumansMaleMiddle AgedObesityProteostasisRNA, Messengerresearch article34545810open access10.7554/eLife.659962050-084XPMC8545398https://doi.org/10.7554/elife.65996https://pmc.ncbi.nlm.nih.gov/articles/PMC8545398/pdf