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.