Isoform-specific regulation of adipocyte differentiation by Akt/protein kinase Balpha.

The phosphatidylinositol 3-kinase (PI3K)/Akt pathway tightly regulates adipose cell differentiation. Here we show that loss of Akt1/PKBalpha in primary mouse embryo fibroblast (MEF) cells results in a defect of adipocyte differentiation. Adipocyte differentiation in vitro and ex vivo was restored in cells lacking both Akt1/PKBalpha and Akt2/PKBbeta by ectopic expression of Akt1/PKBalpha but not Akt2/PKBbeta. Akt1/PKBalpha was found to be the major regulator of phosphorylation and nuclear export of FoxO1, whose presence in the nucleus strongly attenuates adipocyte differentiation. Differentiation-induced cell division was significantly abrogated in Akt1/PKBalpha-deficient cells, but was restored after forced expression of Akt1/PKBalpha. Moreover, expression of p27(Kip1), an inhibitor of the cell cycle, was down regulated in an Akt1/PKBalpha-specific manner during adipocyte differentiation. Based on these data, we suggest that the Akt1/PKBalpha isoform plays a major role in adipocyte differentiation by regulating FoxO1 and p27(Kip1).