Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease.
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Date
2021-09-21
Authors
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.
Description
MeSH Terms
Adipocytes
Adipogenesis
Adult
Cell Differentiation
Cell Line
Diabetes Mellitus, Type 2
Female
Humans
Male
Middle Aged
Obesity
Proteostasis
RNA, Messenger
Adipogenesis
Adult
Cell Differentiation
Cell Line
Diabetes Mellitus, Type 2
Female
Humans
Male
Middle Aged
Obesity
Proteostasis
RNA, Messenger
DeCS Terms
CIE Terms
Keywords
ER-proteostasis, ERAD, RNA splicing, UPR, cell biology, human, obesity-related metabolic diseases, preadipocytes