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

  1. Julia Sánchez-Ceinos
  2. Rocío Guzmán-Ruiz
  3. Oriol Alberto Rangel-Zuñiga
  4. Jaime López-Alcalá
  5. Elena Moreno-Caño
  6. Mercedes del Río-Moreno
  7. Juan Luis Romero-Cabrera
  8. Pablo Pérez-Martínez
  9. Elsa Maymo-Masip
  10. Joan Vendrell
  11. Sonia Fernández-Veledo
  12. José Manuel Fernández-Real
  13. Jurga Laurencikiene
  14. Mikael Rydén
  15. Antonio Membrives
  16. Raul M Luque
  17. José López-Miranda
  18. María M Malagón  Is a corresponding author
  1. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Spain
  2. Hospital Universitari de Tarragona Joan XXIII, Spain
  3. Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, Spain
  4. Institut d'Investigaci ´o Biom`edica de Girona, Spain
  5. Karolinska Institute, Sweden
  6. Reina Sofia University Hospital, Spain
  7. 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.

The following data sets were generated

Article and author information

Author details

  1. Julia Sánchez-Ceinos

    Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Rocío Guzmán-Ruiz

    Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Oriol Alberto Rangel-Zuñiga

    Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Jaime López-Alcalá

    Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Elena Moreno-Caño

    Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Mercedes del Río-Moreno

    Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Juan Luis Romero-Cabrera

    Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Pablo Pérez-Martínez

    Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Elsa Maymo-Masip

    Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Joan Vendrell

    Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, Hospital Universitari de Tarragona Joan XXIII, Tarragona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. Sonia Fernández-Veledo

    Institut d´Investigació Sanitària Pere Virgili Universitat Rovira i Virgili, Tarragona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  12. José Manuel Fernández-Real

    Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigaci ´o Biom`edica de Girona, Girona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  13. Jurga Laurencikiene

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  14. Mikael Rydén

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
  15. Antonio Membrives

    Unidad de Gestión Clínica de Cirugía General y Digestivo, Reina Sofia University Hospital, Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  16. Raul M Luque

    Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofia, and CIBER Fisiopatología de la Obes, Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  17. José López-Miranda

    Lipids and Atherosclerosis Unit, Department of Internal Medicine, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    Competing interests
    The authors declare that no competing interests exist.
  18. María M Malagón

    Department of Cell Biology, Physiology, and Immunology, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
    For correspondence
    bc1mapom@uco.es
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2419-2727

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.

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

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).

Version history

  1. Received: December 21, 2020
  2. Preprint posted: January 17, 2021 (view preprint)
  3. Accepted: September 20, 2021
  4. Accepted Manuscript published: September 21, 2021 (version 1)
  5. Version of Record published: October 25, 2021 (version 2)
  6. Version of Record updated: December 3, 2021 (version 3)

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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  1. Julia Sánchez-Ceinos
  2. Rocío Guzmán-Ruiz
  3. Oriol Alberto Rangel-Zuñiga
  4. Jaime López-Alcalá
  5. Elena Moreno-Caño
  6. Mercedes del Río-Moreno
  7. Juan Luis Romero-Cabrera
  8. Pablo Pérez-Martínez
  9. Elsa Maymo-Masip
  10. Joan Vendrell
  11. Sonia Fernández-Veledo
  12. José Manuel Fernández-Real
  13. Jurga Laurencikiene
  14. Mikael Rydén
  15. Antonio Membrives
  16. Raul M Luque
  17. José López-Miranda
  18. María M Malagón
(2021)
Impaired mRNA splicing and proteostasis in preadipocytes in obesity-related metabolic disease
eLife 10:e65996.
https://doi.org/10.7554/eLife.65996

Share this article

https://doi.org/10.7554/eLife.65996

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