Impaired mRNA splicing and proteostasis in preadipocytes in obesity related metabolic disease

Identifier:  imarina:9230389

Handle: https://hdl.handle.net/20.500.11797/imarina9230389

Authors:  Sánchez-Ceinos, J; Guzmán-Ruiz, R; Rangel-Zúñiga, OA; López-Alcalá, J; Moreno-Caño, E; Del Río-Moreno, M; Romero-Cabrera, JL; Pérez-Martínez, P; Maymo-Masip, E; Vendrell, J; Fernández-Veledo, S; Fernández-Real, JM; Laurencikiene, J; Rydén, M; Membrives, A; Luque, RM; López-Miranda, J; Malagón, MM

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.