Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism

J Clin Invest. 2005 Mar;115(3):718-27. doi: 10.1172/JCI23187.


Hepatic insulin resistance is a critical component in the development of type 2 diabetes mellitus. In many cases, insulin resistance in liver is associated with reduced expression of both major insulin receptor substrate (IRS) proteins, IRS-1 and IRS-2. To investigate the specific functions of IRS-1 and IRS-2 in regulating liver function in vivo, we developed an adenovirus-mediated RNA interference technique in which short hairpin RNAs (shRNAs) are used to knock down IRS-1, IRS-2, or both, by 70-80% in livers of WT mice. The knockdown of IRS-1 resulted in an upregulation of the gluconeogenic enzymes glucose-6 phosphatase and phosphoenolpyruvate carboxykinase, as well as a marked increase in hepatic nuclear factor-4 alpha. Decreased IRS-1 was also associated with a decrease in glucokinase expression and a trend toward increased blood glucose, whereas knockdown of IRS-2 resulted in the upregulation of lipogenic enzymes SREBP-1c and fatty acid synthase, as well as increased hepatic lipid accumulation. The concomitant injection of IRS-1 and IRS-2 adenoviral shRNAs resulted in systemic insulin resistance, glucose intolerance, and hepatic steatosis. The alterations in the dual-knockdown mice were associated with defective Akt activation and Foxo1 phosphorylation. Taken together, our results demonstrate that hepatic IRS-1 and IRS-2 have complementary roles in the control of hepatic metabolism, with IRS-1 more closely linked to glucose homeostasis and IRS-2 more closely linked to lipid metabolism.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism
  • Adipocytes / metabolism
  • Animals
  • Enzyme Activation
  • Fatty Acids / metabolism
  • Gene Expression Regulation
  • Gluconeogenesis / genetics
  • Gluconeogenesis / physiology
  • Glucose / metabolism
  • Homeostasis
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Leptin / metabolism
  • Liver / cytology
  • Liver / metabolism*
  • Liver / pathology
  • Liver / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • RNA Interference*
  • RNA, Small Interfering / chemistry
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism


  • Fatty Acids
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Leptin
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • Phosphatidylinositol 3-Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose