Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

Diabetologia. 2013 Jun;56(6):1372-82. doi: 10.1007/s00125-013-2867-3. Epub 2013 Mar 5.


Aims/hypothesis: Although the substitution of saturated fatty acids with oleate has been recommended in the management of type 2 diabetes mellitus, the mechanisms by which oleate improves insulin resistance in skeletal muscle cells are not completely known. Here, we examined whether oleate, through activation of AMP-activated protein kinase (AMPK), prevented palmitate-induced endoplasmic reticulum (ER) stress, which is involved in the link between lipid-induced inflammation and insulin resistance.

Methods: Studies were conducted in mouse C2C12 myotubes and in the human myogenic cell line LHCN-M2. To analyse the involvement of AMPK, activators and inhibitors of this kinase and overexpression of a dominant negative AMPK construct (K45R) were used.

Results: Palmitate increased the levels of ER stress markers, whereas oleate did not. In palmitate-exposed cells incubated with a lower concentration of oleate, the effects of palmitate were prevented. The induction of ER stress markers by palmitate was prevented by the presence of the AMPK activators AICAR and A-769662. Moreover, the ability of oleate to prevent palmitate-induced ER stress and inflammation (nuclear factor-kappa B [NF-κB] DNA-binding activity and expression and secretion of IL6) as well as insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake was reversed in the presence of the AMPK inhibitor compound C or by overexpression of a dominant negative AMPK construct. Finally, palmitate reduced phospho-AMPK levels, whereas this was not observed in oleate-exposed cells or in palmitate-exposed cells supplemented with oleate.

Conclusions/interpretation: Overall, these findings indicate that oleate prevents ER stress, inflammation and insulin resistance in palmitate-exposed skeletal muscle cells by activating AMPK.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Biphenyl Compounds
  • Cell Line
  • Cell Nucleus / metabolism
  • Chromatography, High Pressure Liquid
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Inflammation / metabolism
  • Insulin Resistance*
  • Lipids / chemistry
  • Mice
  • Muscle Cells / metabolism
  • Muscle, Skeletal / cytology*
  • NF-kappa B / metabolism
  • Oleic Acid / pharmacology*
  • Palmitic Acid / adverse effects*
  • Palmitic Acid / pharmacology
  • Pyrones / pharmacology
  • Ribonucleotides / pharmacology
  • Signal Transduction
  • Thiophenes / pharmacology


  • Biphenyl Compounds
  • Lipids
  • NF-kappa B
  • Pyrones
  • Ribonucleotides
  • Thiophenes
  • Oleic Acid
  • Palmitic Acid
  • Aminoimidazole Carboxamide
  • Adenylate Kinase
  • AICA ribonucleotide
  • 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile