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

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2021-09-21

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Sánchez-Ceinos, Julia
Guzmán-Ruiz, Rocío
Rangel-Zúñiga, Oriol Alberto
López-Alcalá, Jaime
Moreno-Caño, Elena
Del Río-Moreno, Mercedes
Romero-Cabrera, Juan Luis
Pérez-Martínez, Pablo
Maymo-Masip, Elsa
Vendrell, Joan

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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.

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MeSH Terms

Adipocytes
Adipogenesis
Adult
Cell Differentiation
Cell Line
Diabetes Mellitus, Type 2
Female
Humans
Male
Middle Aged
Obesity
Proteostasis
RNA, Messenger

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Keywords

ER-proteostasis, ERAD, RNA splicing, UPR, cell biology, human, obesity-related metabolic diseases, preadipocytes

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