Transforming G protein-coupled receptors block insulin and ras-induced adipocytic differentiation in 3T3-L1 cells:: Evidence for a PKC and MAP kinase independent pathway

We have used the expression of muscarinic m1 receptors in the preadipocytic 3T3-L1 cell line for dissecting the nature of the G protein-linked pathways governing adipocytic differentiation, a complex process controlled by many stimuli and their downstream targets. 3T3-L1 cells can be differentiated by insulin or by ras oncogenes, and MAP kinase has been implicated in this process. However, mi stimulation failed to induce differentiation of 3T3-L1 cells. Furthermore, it prevented insulin or v-ras-induced adipocytic differentiation, utilizing a protein kinase C-independent pathway. mi stimulation did not alter the phosphorylation state of the insulin receptor substrates IRS-1 and SHC, nor the recruitment of Grb-S. Interestingly, whereas mi receptors potently activated MAP kinase, another differentiation-inhibitor, TNF alpha, did not affect it. These results suggest that the control of adipocytic differentiation can occur utilizing a biochemical route independent of protein kinase C, and acting downstream, or independently from the Ras-MAP kinase pathway. (C) 1998 Academic Press.