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 preadipo cytic 3T3-L1 cell line for dissecting the nature of the G protein-link ed pathways governing adipocytic differentiation, a complex process co ntrolled by many stimuli and their downstream targets. 3T3-L1 cells ca n be differentiated by insulin or by ras oncogenes, and MAP kinase has been implicated in this process. However, mi stimulation failed to in duce differentiation of 3T3-L1 cells. Furthermore, it prevented insuli n or v-ras-induced adipocytic differentiation, utilizing a protein kin ase C-independent pathway. mi stimulation did not alter the phosphoryl ation state of the insulin receptor substrates IRS-1 and SHC, nor the recruitment of Grb-S. Interestingly, whereas mi receptors potently act ivated MAP kinase, another differentiation-inhibitor, TNF alpha, did n ot affect it. These results suggest that the control of adipocytic dif ferentiation can occur utilizing a biochemical route independent of pr otein kinase C, and acting downstream, or independently from the Ras-M AP kinase pathway. (C) 1998 Academic Press.