Decreased IRS-2 and Increased SREBP-1c Lead to Mixed Insulin Resistance and Sensitivity in Livers of Lipodystrophic and ob/ob Mice

Mol Cell. 2000 Jul;6(1):77-86.

Abstract

In mice with too little fat (lipodystrophy) or too much fat (ob/ob), leptin deficiency leads to hyperglycemia, hyperinsulinemia, and insulin resistance. In both disorders, the liver overproduces glucose as a result of resistance to the normal action of insulin in repressing mRNAs for gluconeogenic enzymes. Here we show that chronic hyperinsulinemia downregulates the mRNA for IRS-2, an essential component of the insulin-signaling pathway in liver, thereby producing insulin resistance. Despite IRS-2 deficiency, insulin continues to stimulate production of SREBP-1c, a transcription factor that activates fatty acid synthesis. The combination of insulin resistance (inappropriate gluconeogenesis) and insulin sensitivity (elevated lipogenesis) establishes a vicious cycle that aggravates hyperinsulinemia and insulin resistance in lipodystrophic and ob/ob mice.

Publication types

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

MeSH terms

  • Animals
  • Base Sequence
  • CCAAT-Enhancer-Binding Proteins*
  • DNA Primers / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression / drug effects
  • Glucagon / pharmacology
  • Humans
  • In Vitro Techniques
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology*
  • Intracellular Signaling Peptides and Proteins
  • Lipodystrophy / genetics
  • Lipodystrophy / metabolism*
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Mice, Transgenic
  • Models, Biological
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Obesity / genetics
  • Obesity / metabolism*
  • Phosphoproteins / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*

Substances

  • CCAAT-Enhancer-Binding Proteins
  • DNA Primers
  • DNA-Binding Proteins
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs1 protein, rat
  • Irs2 protein, mouse
  • Irs2 protein, rat
  • Nuclear Proteins
  • Phosphoproteins
  • RNA, Messenger
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Glucagon