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Impact of lipid phosphatases SHIP2 and PTEN on the time- and Akt-isoform-specific amelioration of TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes.

Abstract
TNF-alpha is a major contributor to the pathogenesis of insulin resistance associated with obesity and inflammation by serine phosphorylating and degrading insulin receptor substrate-1. Presently, we further found that pretreatment with TNF-alpha inhibited insulin-induced phosphorylation of Akt2 greater than Akt1. Since lipid phosphatases SH2-containing inositol 5'-phoshatase 2 (SHIP2) and phosphatase and tensin homologs deleted on chromosome 10 (PTEN) are negative regulators of insulin's metabolic signaling at the step downstream of phosphatidylinositol 3-kinase, we investigated the Akt isoform-specific properties of these phosphatases in the negative regulation after short- and long-term insulin treatment and examined the influence of inhibition on the amelioration of insulin resistance caused by TNF-alpha in 3T3-L1 adipocytes. Adenovirus-mediated overexpression of WT-SHIP2 decreased the phosphorylation of Akt2 greater than Akt1 after insulin stimulation up to 15 min. Expression of a dominant-negative DeltaIP-SHIP2 enhanced the phosphorylation of Akt2 up to 120 min. On the other hand, overexpression of WT-PTEN inhibited the phosphorylation of both Akt1 and Akt2 after short- but not long-term insulin treatment. The expression of DeltaIP-PTEN enhanced the phosphorylation of Akt1 at 120 min and that of Akt2 at 2 min. Interestingly, the expression of DeltaIP-SHIP2, but not DeltaIP-PTEN, protected against the TNF-alpha inhibition of insulin-induced phosphorylation of Akt2, GSK3, and AS160, whereas both improved the TNF-alpha inhibition of insulin-induced 2-deoxyglucose uptake. The results indicate that these lipid phosphatases possess different characteristics according to the time and preference of Akt isoform-dependent signaling in the negative regulation of the metabolic actions of insulin, whereas both inhibitions are effective in the amelioration of insulin resistance caused by TNF-alpha.
AuthorsMariko Ikubo, Tsutomu Wada, Kazuhito Fukui, Manabu Ishiki, Hajime Ishihara, Tomoichiro Asano, Hiroshi Tsuneki, Toshiyasu Sasaoka
JournalAmerican journal of physiology. Endocrinology and metabolism (Am J Physiol Endocrinol Metab) Vol. 296 Issue 1 Pg. E157-64 (Jan 2009) ISSN: 0193-1849 [Print] United States
PMID19001549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • GTPase-Activating Proteins
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Tbc1d4 protein, mouse
  • Tumor Necrosis Factor-alpha
  • Deoxyglucose
  • Akt1 protein, mouse
  • Akt2 protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases
  • PTEN Phosphohydrolase
  • Pten protein, mouse
  • Inppl1 protein, mouse
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Topics
  • 3T3-L1 Cells
  • Adipocytes (drug effects, enzymology, metabolism)
  • Animals
  • Deoxyglucose (metabolism)
  • GTPase-Activating Proteins (metabolism)
  • Glycogen Synthase Kinase 3 (metabolism)
  • Inositol Polyphosphate 5-Phosphatases
  • Insulin (metabolism, pharmacology)
  • Insulin Receptor Substrate Proteins (metabolism)
  • Insulin Resistance (physiology)
  • Mice
  • PTEN Phosphohydrolase (biosynthesis, genetics, metabolism)
  • Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
  • Phosphoric Monoester Hydrolases (biosynthesis, genetics, metabolism)
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt (metabolism)
  • Transfection
  • Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism, pharmacology)

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