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

Jingyu Huang, Judith Simcox, T. Creighton Mitchell, Deborah Jones, James Cox, Bai Luo, Robert C. Cooksey, Laszlo G. Boros, Donald A. McClain

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2845-2854
Number of pages10
JournalFASEB Journal
Volume27
Issue number7
DOIs
StatePublished - Jul 2013
Externally publishedYes

Keywords

  • Acetylation
  • AMPK
  • Insulin signaling

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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