Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes

Nature. 2004 Dec 23;432(7020):1027-32. doi: 10.1038/nature03047.


The regulation of fat and glucose metabolism in the liver is controlled primarily by insulin and glucagon. Changes in the circulating concentrations of these hormones signal fed or starvation states and elicit counter-regulatory responses that maintain normoglycaemia. Here we show that in normal mice, plasma insulin inhibits the forkhead transcription factor Foxa2 by nuclear exclusion and that in the fasted (low insulin) state Foxa2 activates transcriptional programmes of lipid metabolism and ketogenesis. In insulin-resistant or hyperinsulinaemic mice, Foxa2 is inactive and permanently located in the cytoplasm of hepatocytes. In these mice, adenoviral expression of Foxa2T156A, a nuclear, constitutively active Foxa2 that cannot be inhibited by insulin, decreases hepatic triglyceride content, increases hepatic insulin sensitivity, reduces glucose production, normalizes plasma glucose and significantly lowers plasma insulin. These changes are associated with increased expression of genes encoding enzymes of fatty acid oxidation, ketogenesis and glycolysis. Chronic hyperinsulinaemia in insulin-resistant syndromes results in the cytoplasmic localization and inactivation of Foxa2, thereby promoting lipid accumulation and insulin resistance in the liver. Pharmacological intervention to inhibit phosphorylation of Foxa2 may be an effective treatment for type 2 diabetes.

Publication types

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

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / pathology
  • Fasting* / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Glucose / metabolism
  • Hepatocyte Nuclear Factor 3-beta
  • Humans
  • Hyperinsulinism / blood
  • Hyperinsulinism / metabolism
  • Hyperinsulinism / pathology
  • Insulin / blood
  • Insulin / physiology
  • Insulin Resistance
  • Ketone Bodies / biosynthesis
  • Ketone Bodies / metabolism*
  • Lipid Metabolism*
  • Liver / cytology
  • Liver / metabolism*
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mitochondria / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Oxidation-Reduction
  • Phosphorylation
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • FOXA2 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Foxa2 protein, mouse
  • Foxo1 protein, mouse
  • Insulin
  • Ketone Bodies
  • Nuclear Proteins
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Hepatocyte Nuclear Factor 3-beta
  • Glucose