Phorbol 12-myristate 13-acetate inhibits the antilipolytic action of insulin, probably via the activity of protein kinase Cε.
Protein kinase CβI (PKCβI) mediates insulin signaling and attenuates β1-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 β3-adrenoceptor agonist CL 316243. PMA inhibited the insulin antilipolytic action. The pan-PKC inhibitors GF 109203X and chelerythrine inhibited the PMA effect, but the PKCα/β inhibitors Gö 6976 and CGP 53353 did not. Exposure of cells to PMA downregulated PKCs α, βI, and δ within 3 h and PKCε within 12 h. The effect of PMA on insulin action greatly diminished when PKCε 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 β 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 PKCε.
Nakamura
Jiro
J
Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba-shi, Ibaraki-ken, 305-8575, Japan. jnakamur@md.tsukuba.ac.jp
D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology
D007328:Insulin; D007329:Insulin Antagonists; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; C016658:phorbolol myristate acetate; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517294:Pde3b protein, rat; D013755:Tetradecanoylphorbol Acetate