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 M.López-Miranda, JoséMalagón, María M.2022-12-122022-12-122021-09-21Sánchez-Ceinos J, Guzmán-Ruiz R, Rangel-Zúñiga OA, López-Alcalá J, Moreno-Caño E, Del Río-Moreno M, et al. Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease. Elife. 2021 Sep 21;10:e65996http://hdl.handle.net/10668/4480Preadipocytes 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.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/mRNAProteostasisAdipocytesObesityMetabolic diseaseTissue expansionARN mensajeroAdipocitosObesidadEnfermedades metabólicasExpansión de tejidoMedical Subject Headings::Anatomy::Cells::Connective Tissue Cells::AdipocytesMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Differentiation::AdipogenesisMedical Subject Headings::Persons::Persons::Age Groups::AdultMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell DifferentiationMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell LineMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Glucose Metabolism Disorders::Diabetes Mellitus::Diabetes Mellitus, Type 2Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Persons::Persons::Age Groups::Adult::Middle AgedMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Nutrition Disorders::Overnutrition::ObesityMedical Subject Headings::Chemicals and Drugs::Nucleic Acids, Nucleotides, and Nucleosides::Nucleic Acids::RNA::RNA, MessengerMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseases::Proteostasis DeficienciesMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Surgical Procedures, Operative::Reconstructive Surgical Procedures::Tissue ExpansionMedical Subject Headings::Diseases::Nutritional and Metabolic Diseases::Metabolic Diseasesresearch article34545810open access10.7554/eLife.659962050-084XPMC8545398