Long-chain n-3 polyunsaturated fatty acids dissociate phosphorylation of Akt from phosphatidylinositol 3′-kinase activity in rats

We examined whether a low amount of dietary long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) modulated phosphatidylinositol 3'-kinase (PI 3-kinase) activity and downstream Akt phosphorylation differently in normal or insulin-resistant rats. Rats were fed for 28 days with either a control diet containing 14.6% of metabolizable energy (ME) as peanut-rape oil ( PR) or an n-3 diet where 4.9% of ME as PR was replaced by fish oil. Over the last 5 days, rats received 9 parts per thousand NaCl or dexamethasone (1 mg/kg). Insulin stimulation of both PI 3-kinase activity and Akt serine(473) phosphorylation and modulation of GLUT4 content were studied in liver, muscle, and adipose tissue ( AT). Glucose tolerance and insulin sensitivity were determined by an oral glucose challenge. In muscle and AT, LC n-3 PUFA abolished insulin-stimulated PI 3-kinase activity. These effects were not paralleled by defects in Akt serine473 phosphorylation, which was even increased in AT. Dexamethasone abolished insulin-stimulated PI 3-kinase activity in all tissues, whereas Akt serine473 phosphorylation was markedly reduced in muscle but unaltered in liver and AT. Such tissue-specific dissociating effects of LC n-3 PUFA on PI 3-kinase/ Akt activation took place without alteration of glucose metabolism. Maintenance of a normal glucose metabolism by the n-3 diet despite abolition of PI 3-kinase activation was likely explained by a compensatory downstream Akt serine473 phosphorylation. The inability of LC n-3 PUFA to prevent insulin resistance by dexamethasone could result from the lack of such a dissociation.