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

Diabetologia. 2014 Oct;57(10):2126-35. doi: 10.1007/s00125-014-3331-8. Epub 2014 Jul 26.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Line
  • Diet, High-Fat / adverse effects
  • Endoplasmic Reticulum Stress / genetics
  • Endoplasmic Reticulum Stress / physiology*
  • Humans
  • In Vitro Techniques
  • Inflammation / etiology
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Mice
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • PPAR delta / deficiency
  • PPAR delta / genetics
  • PPAR delta / physiology*
  • PPAR-beta / deficiency
  • PPAR-beta / genetics
  • PPAR-beta / physiology*


  • PPAR delta
  • PPAR-beta
  • AMP-Activated Protein Kinases