Phorbol 12-myristate 13-acetate inhibits the antilipolytic action of insulin, probably via the activity of protein kinase Cepsilon.

摘要

Protein kinase CbetaI (PKCbetaI) mediates insulin signaling and attenuates beta1-adrenoceptor-stimulated lipolysis. In this work, the effect of the PKC activator phorbol 12-myristate 13-acetate (PMA) on the antilipolytic action of insulin was determined by analyzing lipolysis induced by a beta3-adrenoceptor agonist CL 316243. PMA inhibited the insulin antilipolytic action. The pan-PKC inhibitors GF 109203X and chelerythrine inhibited the PMA effect, but the PKCalpha/beta inhibitors Go 6976 and CGP 53353 did not. Exposure of cells to PMA downregulated PKCs alpha, betaI, and delta within 3 h and PKCepsilon within 12 h. The effect of PMA on insulin action greatly diminished when PKCepsilon was downregulated. Inhibitors of phosphatidylinositol 3-kinase (PI3-K), Akt, and phosphodiesterase 3B (PDE3B) diminished the PMA effect. PMA inhibited insulin-stimulated phosphorylation of Tyr in insulin receptor beta subunit and Ser/Thr in Akt. These data suggest that PMA inhibits the antilipolytic signal mediated by the insulin receptor, PI3-K, Akt, and PDE3B. The most probable target of PMA is PKCepsilon.