Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
- Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Spain
- Hospital Universitari de Tarragona Joan XXIII, Spain
- Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, Spain
- Institut d'Investigaci ´o Biom`edica de Girona, Spain
- Karolinska Institute, Sweden
- Reina Sofia University Hospital, Spain
- University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, and CIBER Fisiopatología de la Obes, Spain
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.
Data availability
All the proteomic data related to this study are available at the ProteomeXchange Consortium via the Proteomics IDEntifications (PRIDE) partner repository with the dataset identifier PXD015621.All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 and 3.
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Funding
Ministerio de Ciencia, Innovación y Universidades (BFU2013-44229-R)
- María M Malagón
Instituto de Salud Carlos III (CP10/ 00438)
- Sonia Fernández-Veledo
Instituto de Salud Carlos III (CPII16/00008)
- Sonia Fernández-Veledo
European Social Fund (BIO-0139)
- María M Malagón
Ministerio de Ciencia, Innovación y Universidades (BFU2016-76711-R)
- María M Malagón
Ministerio de Ciencia, Innovación y Universidades (BFU2017-90578-REDT)
- María M Malagón
Ministerio de Ciencia, Innovación y Universidades (´RTI2018-093919-B-I00)
- Sonia Fernández-Veledo
Junta de Andalucía (PI-0200/2013)
- María M Malagón
Junta de Andalucía (PI-0159-2016)
- Rocío Guzmán-Ruiz
Instituto de Salud Carlos III (PIE14/00005)
- María M Malagón
Instituto de Salud Carlos III (PI16/00264)
- Raul M Luque
Instituto de Salud Carlos III (PI17/0153)
- Joan Vendrell
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: Written consent was obtained from all the participants prior to recruitment, and the experimental protocol was approved by the Ethics and Research Committee of corresponding hospitals following the Helsinki Declaration (ref. 3170).
Copyright
© 2021, Sánchez-Ceinos et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
eLife 10:e65996.
https://doi.org/10.7554/eLife.65996
