Iron regulates glucose homeostasis in liver and muscle via AMP-activated protein kinase in mice

FASEB J. 2013 Jul;27(7):2845-54. doi: 10.1096/fj.12-216929. Epub 2013 Mar 20.

Abstract

Excess iron is associated with hepatic damage and diabetes in humans, although the detailed molecular mechanisms are not known. To investigate how iron regulates glucose homeostasis, we fed C57BL/6J male mice with high-iron (HI) diets (2 or 20 g Fe/kg chow). Mice fed an HI diet exhibited elevated AMP-activated protein kinase (AMPK) activity and impaired insulin signaling in skeletal muscle and liver. Consistent with the increased AMPK activity, glucose uptake was enhanced in mice fed an HI diet. The effects of improved glucose tolerance induced by HI feeding were abolished in transgenic mice with expression of muscle specific dominant-negative AMPK. Glucose output was suppressed in the liver of wild-type mice fed an HI diet, due to decreased expression of gluconeogenic genes and decreased substrate (lactate) from peripheral glycolysis. Iron activated AMPK by increasing deacetylase and decreasing LKB1 acetylation, in turn stimulating the phosphorylation of LKB1 and AMPK. The effects of HI diet were abrogated by treatment of the mice with N-acetyl cysteine, suggesting a redox-dependent mechanism for increasing deacetylase activity. In addition, tissue from iron-fed mice exhibited an elevated AMP/ATP ratio, further contributing to AMPK activation. In summary, a diet high in iron improves glucose tolerance by activating AMPK through mechanisms that include deacetylation.

Keywords: AMPK; acetylation; insulin signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Acetylation / drug effects
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Blotting, Western
  • Cell Differentiation / drug effects
  • Cell Line
  • Diet
  • Enzyme Activation / drug effects
  • Gene Expression / drug effects
  • Gluconeogenesis / genetics
  • Glucose / metabolism*
  • Homeostasis / drug effects*
  • Iron / administration & dosage
  • Iron / metabolism
  • Iron / pharmacology*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism*
  • Myoblasts / cytology
  • Myoblasts / drug effects
  • Myoblasts / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • Iron
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases
  • Glucose