Inhibition of cAMP-response element-binding protein activity decreases protein kinase B/Akt expression in 3T3-L1 adipocytes and induces apoptosis.

White adipose tissue mass is governed by competing processes that control lipid synthesis and storage, the development of new adipocytes, and their survival. We have shown that the transcription factor cAMP-response element-binding protein (CREB) participates in adipogenesis, with constitutively active forms of CREB inducing adipocyte differentiation and dominant negative forms of CREB blocking this process. In other cell types, CREB and related factors have been shown to play important roles in survival and apoptosis. Here we demonstrate that reduction of CREB activity by ectopic expression of the dominant negative CREB, KCREB, induces apoptosis of mature 3T3-L1 adipocytes in culture. Death by apoptosis was confirmed by increased nuclear condensation, changes in membrane morphology, and increased DNA fragmentation. Gene microarray analysis indicated that KCREB expression increased expression of several pro-apoptotic genes like Interleukin Converting Enzyme and decreased the expression of the anti-apoptotic signaling molecule, Akt/protein kinase B. Finally, introduction of constitutively active CREB, CREB-DIEDML, blocked death of mature adipocytes treated with TNF-alpha. The data indicate that CREB plays a central role in adipocyte survival, perhaps by regulating the expression of certain pro- and anti-apoptotic genes. These results not only extend the role of CREB in adipocyte biology but also highlight the general developmental and survival role of this factor in numerous cell and tissue types.