The G_sα/G_1α2 axis controls adipogenesis independently of adenylylcyclase

Adipogenesis is the commitment of embryonic stem cells to the highly-differentiated phenotype of the adipocyte, a cell specialized to regulate, in a dynamic fashion, lipid storage. The mouse embryonic 3T3-L1 fibroblasts provide a useful model in which to probe the control of differentiation in general and adipogenesis in particular. The G-proteins G_sα and G_iα2 have been shown to modulate commitment of fibroblasts to adipocytes in response to inducers such as dexamethasone and methylisobutylxanthine. Cellular levels of G_sα decline sharply in response to inducers as cells commit to the adipogenic phenotype. The molecular strategies of antisense DNA technology and expression of constitutively-activated mutants of G_iα2 reveal that either suppression of G_sα or expression of constitutively-active G_iα2 dramatically accelerate the ability of inducers to stimulate adipogenesis or act as inducers themselves. These roles of G_sα and G_iα2 are expressed in ambient or elevated intracellular cyclic AMP, demonstrating a critical role of G-proteins in cellular differentiation independent of adenylylcyclase.