Okadaic acid inhibits insulin-induced glucose transport in fetal brown adipocytes in an Akt-independent and protein kinase C zeta-dependent manner

FEBS Lett. 2000 Apr 21;472(1):153-8. doi: 10.1016/s0014-5793(00)01448-4.

Abstract

In the present study we have investigated the effect of increased serine/threonine phosphorylation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) by okadaic acid pretreatment on brown adipocyte insulin signalling leading to glucose transport, an important metabolic effect of insulin in brown adipose tissue. Okadaic acid pretreatment before insulin stimulation decreased IRS-1 and IRS-2 tyrosine phosphorylation in parallel to a decrease in their sodium dodecyl sulfate-polyacrylamide gel electrophoresis mobility. IRS-1/IRS-2-associated p85alpha and phosphatidylinositol (PI) 3-kinase enzymatic activity were partly reduced in brown adipocytes pretreated with okadaic acid upon stimulation with insulin. Furthermore, insulin-induced glucose uptake was totally abolished by the inhibitor in parallel with a total inhibition of insulin-induced protein kinase C (PKC) zeta activity. However, activation of Akt/PKB or p70 S6 kinase (p70(s6k)) by insulin remained unaltered. Our results suggest that downstream of PI 3-kinase, insulin signalling diverges into at least two independent pathways through Akt/PKB and PKC zeta, the PKC zeta pathway contributing to glucose transport induced by insulin in fetal brown adipocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / cytology
  • Adipose Tissue, Brown / enzymology
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology*
  • Fetus
  • Glucose / metabolism*
  • Humans
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes / metabolism
  • Okadaic Acid / pharmacology*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase C / metabolism*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Rats
  • Rats, Wistar
  • Receptor, Insulin / metabolism
  • Ribosomal Protein S6 Kinases / metabolism

Substances

  • Enzyme Inhibitors
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, rat
  • Irs2 protein, rat
  • Isoenzymes
  • Phosphoproteins
  • Proto-Oncogene Proteins
  • Okadaic Acid
  • Receptor, Insulin
  • AKT1 protein, human
  • Akt1 protein, rat
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Ribosomal Protein S6 Kinases
  • protein kinase C zeta
  • Protein Kinase C
  • Glucose