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- Title
Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease.
- Authors
Sánchez-Ceinos, Julia; Guzmán-Ruiz, Rocío; Rangel-Zúñiga, Oriol Alberto; López-Alcalá, Jaime; Moreno-Caño, Elena; Del Río-Moreno, Mercedes; Luis Romero-Cabrera, Juan; Pérez-Martínez, Pablo; Maymo-Masip, Elsa; Vendrell, Joan; Fernández-Veledo, Sonia; Manuel Fernández-Real, José; Laurencikiene, Jurga; Rydén, Mikael; Membrives, Antonio; Luque, Raul M.; López-Miranda, José; Malagón, María M.
- Abstract
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, 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.
- Subjects
METABOLIC disorders; INSULIN resistance; ADIPOSE tissues; FAT cells; TISSUE expansion; SPLICEOSOMES
- Publication
eLife, 2021, p1
- ISSN
2050-084X
- Publication type
Article
- DOI
10.7554/eLife.65996