Diet-induced Insulin Resistance in Mice Lacking adiponectin/ACRP30

Nat Med. 2002 Jul;8(7):731-7. doi: 10.1038/nm724. Epub 2002 Jun 17.

Abstract

Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiponectin
  • Adipose Tissue / metabolism
  • Animals
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Diet*
  • Fatty Acid-Binding Proteins
  • Fatty Acids, Nonesterified / blood*
  • Fish Proteins*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology*
  • Intercellular Signaling Peptides and Proteins*
  • Lipid Metabolism*
  • Mice
  • Mice, Knockout
  • Myocardium / cytology
  • Myocardium / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / metabolism
  • Proteins / genetics
  • Proteins / physiology*
  • RNA, Messenger / genetics
  • Transcription, Genetic
  • Tumor Necrosis Factor-alpha / genetics*

Substances

  • Adiponectin
  • Carrier Proteins
  • FABP-1 protein, Lateolabrax japonicus
  • Fatty Acid-Binding Proteins
  • Fatty Acids, Nonesterified
  • Fish Proteins
  • Insulin Receptor Substrate Proteins
  • Intercellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Phosphoproteins
  • Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Phosphatidylinositol 3-Kinases