| The insulin signaling pathway is a major regulator of energy homeostasis in the cell. Akt is a serine/threonine kinase acting downstream of the growth factor receptors to regulate numerous cellular processes including proliferation, differentiation and cell death. Knockout models of the different Akt isoforms, especially Akt2, demonstrate their importance in regulating the glucose metabolism in the body. The adipose tissue, along with the skeletal muscle and the liver controls the energy homeostasis at the organismal levels.;We examined the role of Akt in regulating brown adipose tissue differentiation by using immortalized brown preadipocytes obtained from Akt1/2 double knockout embryos as a model system. We show that the regulation of PPARgamma expression is the key step by which Akt controls adipocyte differentiation. Our data demonstrates that the expression of many of the upstream factors that regulate PPARgamma expression and activity is modified in the preadipocytes lacking Akt1 and Akt2. We also show that Akt regulates one of the very early steps in adipocyte differentiation, mitotic clonal expansion. The cells with reduced Akt activity fail to re enter cell cycle after being induced to differentiate and this correlates with a failure to down regulate the cell cycle inhibitors p21 and p27. Preliminary investigations suggest that Akt might regulate p27 and p21 in part through the forkhead transcription factor FoxO and the E3 ubiquitin ligase Skp2. Thus Akt seems to regulate adipocyte differentiation through multiple mechanisms. |
