Foxo1 integrates insulin signaling with mitochondrial function in the liver

Zhiyong Cheng, Shaodong Guo, Kyle Copps, X. Dong, Ramya Kollipara, Joseph T. Rodgers, Ronald A. Depinho, Pere Puigserver, Morris F. White

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

Type 2 diabetes is a complex disease that is marked by the dysfunction of glucose and lipid metabolism. Hepatic insulin resistance is especially pathogenic in type 2 diabetes, as it dysregulates fasting and postprandial glucose tolerance and promotes systemic dyslipidemia and nonalcoholic fatty liver disease. Mitochondrial dysfunction is closely associated with insulin resistance and might contribute to the progression of diabetes. Here we used previously generated mice with hepatic insulin resistance owing to the deletion of the genes encoding insulin receptor substrate-1 (Irs-1) and Irs-2 (referred to here as double-knockout (DKO) mice) to establish the molecular link between dysregulated insulin action and mitochondrial function. The expression of several forkhead box O1 (Foxo1) target genes increased in the DKO liver, including heme oxygenase-1 (Hmox1), which disrupts complex III and IV of the respiratory chain and lowers the NAD+/NADH ratio and ATP production. Although peroxisome proliferator-activated receptor-coactivator-1α (Ppargc-1α) was also upregulated in DKO liver, it was acetylated and failed to promote compensatory mitochondrial biogenesis or function. Deletion of hepatic Foxo1 in DKO liver normalized the expression of Hmox1 and the NAD +/NADH ratio, reduced Ppargc-1α acetylation and restored mitochondrial oxidative metabolism and biogenesis. Thus, Foxo1 integrates insulin signaling with mitochondrial function, and inhibition of Foxo1 can improve hepatic metabolism during insulin resistance and the metabolic syndrome.

Original languageEnglish
Pages (from-to)1307-1311
Number of pages5
JournalNature Medicine
Volume15
Issue number11
DOIs
StatePublished - Nov 2009

Fingerprint

Liver
Insulin
NAD
Medical problems
Insulin Resistance
Heme Oxygenase-1
Metabolism
Type 2 Diabetes Mellitus
Enzyme inhibition
Insulin Receptor Substrate Proteins
Glucose
Acetylation
Peroxisome Proliferator-Activated Receptors
Gene encoding
Electron Transport Complex III
Gene Deletion
Organelle Biogenesis
Dyslipidemias
Electron Transport
Lipid Metabolism

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cheng, Z., Guo, S., Copps, K., Dong, X., Kollipara, R., Rodgers, J. T., ... White, M. F. (2009). Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nature Medicine, 15(11), 1307-1311. https://doi.org/10.1038/nm.2049

Foxo1 integrates insulin signaling with mitochondrial function in the liver. / Cheng, Zhiyong; Guo, Shaodong; Copps, Kyle; Dong, X.; Kollipara, Ramya; Rodgers, Joseph T.; Depinho, Ronald A.; Puigserver, Pere; White, Morris F.

In: Nature Medicine, Vol. 15, No. 11, 11.2009, p. 1307-1311.

Research output: Contribution to journalArticle

Cheng, Z, Guo, S, Copps, K, Dong, X, Kollipara, R, Rodgers, JT, Depinho, RA, Puigserver, P & White, MF 2009, 'Foxo1 integrates insulin signaling with mitochondrial function in the liver', Nature Medicine, vol. 15, no. 11, pp. 1307-1311. https://doi.org/10.1038/nm.2049
Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers JT et al. Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nature Medicine. 2009 Nov;15(11):1307-1311. https://doi.org/10.1038/nm.2049
Cheng, Zhiyong ; Guo, Shaodong ; Copps, Kyle ; Dong, X. ; Kollipara, Ramya ; Rodgers, Joseph T. ; Depinho, Ronald A. ; Puigserver, Pere ; White, Morris F. / Foxo1 integrates insulin signaling with mitochondrial function in the liver. In: Nature Medicine. 2009 ; Vol. 15, No. 11. pp. 1307-1311.
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