Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
Julia Sánchez-Ceinos, Rocío Guzmán‐Ruiz, Oriol Alberto Rangel-Zúñiga, Jaime López‐Alcalá, E. Moreno-Caño, Mercedes del Río-Moreno, Juan Luis Romero‐Cabrera, Pablo Pérez‐Martínez, Elsa Maymó‐Masip, Joan Vendrell, Sonia Fernández‐Veledo, José Manuel Fernández‐Real, Jurga Laurencikiene, Mikael Rydén, Antonio Membrives, Raúl M. Luque, José López-Miranda, Marı́a M. Malagón
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.