Diabetologia

, Volume 57, Issue 10, pp 2126–2135 | Cite as

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

  • Laia Salvadó
  • Emma Barroso
  • Anna Maria Gómez-Foix
  • Xavier Palomer
  • Liliane Michalik
  • Walter Wahli
  • Manuel Vázquez-Carrera
Article

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.

Keywords

AMPK ER stress ERK1/2 NF-κB PPAR β/δ 

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

Supplementary material

125_2014_3331_MOESM1_ESM.pdf (75 kb)
ESM Methods(PDF 75 kb)
125_2014_3331_MOESM2_ESM.pdf (43 kb)
ESM Table 1(PDF 43 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Laia Salvadó
    • 1
    • 2
    • 3
  • Emma Barroso
    • 1
    • 2
    • 3
  • Anna Maria Gómez-Foix
    • 2
    • 3
    • 4
  • Xavier Palomer
    • 1
    • 2
    • 3
  • Liliane Michalik
    • 5
  • Walter Wahli
    • 5
    • 6
  • Manuel Vázquez-Carrera
    • 1
    • 2
    • 3
  1. 1.Department of Pharmacology and Therapeutic Chemistry, Faculty of PharmacyUniversity of BarcelonaBarcelonaSpain
  2. 2.Institute of Biomedicine of the University of Barcelona (IBUB)BarcelonaSpain
  3. 3.Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM), Spain
  4. 4.Department of Biochemistry and Molecular Biology, Faculty of BiologyUniversity of BarcelonaBarcelonaSpain
  5. 5.Center for Integrative Genomics, National Research Center Frontiers in GeneticsUniversity of LausanneLausanneSwitzerland
  6. 6.Lee Kong Chian School of MedicineNanyang Technological UniversitySingaporeRepublic of Singapore

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