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PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

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Abstract

Aim/hypothesis

Endoplasmic reticulum (ER) stress, which is involved in the link between inflammation and insulin resistance, contributes to the development of type 2 diabetes mellitus. In this study, we assessed whether peroxisome proliferator-activated receptor (PPAR)β/δ prevented ER stress-associated inflammation and insulin resistance in skeletal muscle cells.

Methods

Studies were conducted in mouse C2C12 myotubes, in the human myogenic cell line LHCN-M2 and in skeletal muscle from wild-type and PPARβ/δ-deficient mice and mice exposed to a high-fat diet.

Results

The PPARβ/δ agonist GW501516 prevented lipid-induced ER stress in mouse and human myotubes and in skeletal muscle of mice fed a high-fat diet. PPARβ/δ activation also prevented thapsigargin- and tunicamycin-induced ER stress in human and murine skeletal muscle cells. In agreement with this, PPARβ/δ activation prevented ER stress-associated inflammation and insulin resistance, and glucose-intolerant PPARβ/δ-deficient mice showed increased phosphorylated levels of inositol-requiring 1 transmembrane kinase/endonuclease-1α in skeletal muscle. Our findings demonstrate that PPARβ/δ activation prevents ER stress through the activation of AMP-activated protein kinase (AMPK), and the subsequent inhibition of extracellular-signal-regulated kinase (ERK)1/2 due to the inhibitory crosstalk between AMPK and ERK1/2, since overexpression of a dominant negative AMPK construct (K45R) reversed the effects attained by PPARβ/δ activation.

Conclusions/interpretation

Overall, these findings indicate that PPARβ/δ prevents ER stress, inflammation and insulin resistance in skeletal muscle cells by activating AMPK.

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Abbreviations

2-DG:

2-Deoxy-glucose

ACC2:

Acetyl-CoA carboxylase 2

AMPK:

AMP-activated protein kinase

ATF6:

Activating transcription factor-6

eIF2α:

Εukaryotic initiation factor 2α

EMSA:

Electrophoretic mobility shift assay

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

IκB:

Inhibitor of κB

IRE1α:

Inositol-requiring 1 transmembrane kinase/endonuclease-1α

NF-κB:

Nuclear factor-κB

PERK:

Eukaryotic translation initiation factor-2α kinase 3

PPAR:

Peroxisome proliferator-activated receptor

UPR:

Unfolded protein response

XBP1:

X-box binding protein-1

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Acknowledgements

We thank A. Orozco (Department of Biochemistry and Molecular Biology of the University of Barcelona, Spain) for experimental assistance with human myotube cultures. We thank M. J. Birnbaum (Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, PA, USA) for the pcDNA3/pAMPKalpha2-K45R plasmid.

Funding

This study was partly supported by funds from the Spanish Ministerio de Economía y Competitividad (SAF2009-06939 and SAF2012-30708) and the European Union ERDF. CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an Instituto de Salud Carlos III project. LS was supported by an FPI grant from the Spanish Ministerio de Economía y Competitividad. We thank the University of Barcelona’s Language Advisory Service for revising the manuscript.

Contribution statement

LS, EB, AMG-F, XP, LM, WW and MV-C processed the samples, analysed and prepared the data and were involved in drafting the article. LS, EB, AG-F, XP, LM and WW contributed to the interpretation of the data and revised the article. MV-C and LS designed the experiments and analysed and interpreted the data. MV-C wrote the manuscript and is responsible for the integrity of the work as a whole. All authors approved the final version of the manuscript.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Diagonal 643, 08028, Barcelona, Spain

    Laia Salvadó, Emma Barroso, Xavier Palomer & Manuel Vázquez-Carrera

  2. Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain

    Laia Salvadó, Emma Barroso, Anna Maria Gómez-Foix, Xavier Palomer & Manuel Vázquez-Carrera

  3. Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain http://www.ciberdem.org

    Laia Salvadó, Emma Barroso, Anna Maria Gómez-Foix, Xavier Palomer & Manuel Vázquez-Carrera

  4. Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain

    Anna Maria Gómez-Foix

  5. Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Lausanne, Switzerland

    Liliane Michalik & Walter Wahli

  6. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Republic of Singapore

    Walter Wahli

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  1. Laia Salvadó
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Corresponding author

Correspondence to Manuel Vázquez-Carrera.

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Salvadó, L., Barroso, E., Gómez-Foix, A.M. et al. PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia 57, 2126–2135 (2014). https://doi.org/10.1007/s00125-014-3331-8

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