Role of STAT-3 in Regulation of Hepatic Gluconeogenic Genes and Carbohydrate Metabolism in Vivo

Nat Med. 2004 Feb;10(2):168-74. doi: 10.1038/nm980. Epub 2004 Jan 11.

Abstract

The transcription factor, signal transducer and activator of transcription-3 (STAT-3) contributes to various physiological processes. Here we show that mice with liver-specific deficiency in STAT-3, achieved using the Cre-loxP system, show insulin resistance associated with increased hepatic expression of gluconeogenic genes. Restoration of hepatic STAT-3 expression in these mice, using adenovirus-mediated gene transfer, corrected the metabolic abnormalities and the alterations in hepatic expression of gluconeogenic genes. Overexpression of STAT-3 in cultured hepatocytes inhibited gluconeogenic gene expression independently of peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha), an upstream regulator of gluconeogenic genes. Liver-specific expression of a constitutively active form of STAT-3, achieved by infection with an adenovirus vector, markedly reduced blood glucose, plasma insulin concentrations and hepatic gluconeogenic gene expression in diabetic mice. Hepatic STAT-3 signaling is thus essential for normal glucose homeostasis and may provide new therapeutic targets for diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Carbohydrate Metabolism*
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Diabetes Mellitus / metabolism
  • Dietary Fats
  • Gene Transfer Techniques
  • Gluconeogenesis / genetics*
  • Gluconeogenesis / physiology
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Insulin / metabolism
  • Liver / cytology
  • Liver / pathology
  • Liver / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*
  • Transcription Factors / metabolism

Substances

  • Blood Glucose
  • DNA-Binding Proteins
  • Dietary Fats
  • Insulin
  • Receptors, Cell Surface
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1