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

Ikubo M, Wada T, Fukui K, Ishiki M, Ishihara H, Asano T, Tsuneki H, Sasaoka T. 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. Am J Physiol Endocrinol Metab 296: E157-E164, 2009. First published November 11, 2008; doi: 10.1152/ajpendo.90581.2008.-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 Delta IP-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 Delta IP-PTEN enhanced the phosphorylation of Akt1 at 120 min and that of Akt2 at 2 min. Interestingly, the expression of Delta IP-SHIP2, but not Delta IP-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.