THE G(S-ALPHA) G(I-ALPHA-2) AXIS CONTROLS ADIPOGENESIS INDEPENDENTLY OF ADENYLYLCYCLASE/

Adipogenesis is the commitment of embryonic stem cells to the highly-d ifferentiated phenotype of the adipocyte, a cell specialized to regula te. in a dynamic fashion, lipid storage. The mouse embryonic 3T3-L1 fi broblasts provide a useful model in which to probe the control of diff erentiation in general and adipogenesis in particular. The G-proteins G(s alpha) and G(i alpha 2), have been shown to modulate commitment of fibroblasts to adipocytes in response to inducers such as dexamethaso ne and methylisobutylxanthine. Cellular levels of G(s alpha) decline s harply in response to inducers as cells commit to the adipogenic pheno type. The molecular strategies of antisense DNA technology and express ion of constitutively-activated mutants of G(i alpha 2) reveal that ei ther suppression of G(s alpha) or expression of constitutively-active G(i alpha 2) dramatically accelerate the ability of inducers to stimul ate adipogenesis or act as inducers themselves. These roles of Gs alph a and G(i alpha 2) are expressed in ambient or elevated intracellular cyclic AMP, demonstrating a critical role of G-proteins in cellular di fferentiation independent of adenylylcyclase.