REVERSAL OF CHRONIC ALTERATIONS OF SKELETAL-MUSCLE PROTEIN-KINASE-C FROM FAT-FED RATS BY BRL-49653

We have recently shown that the reduction in insulin sensitivity of ra ts fed a high-fat diet is associated with the translocation of the nov el protein kinase C-epsilon (nPKC(epsilon)) from cytosolic to particul ate fractions in red skeletal muscle and also the downregulation of cy tosolic nPKC(theta). Here we have further investigated the link betwee n insulin resistance and PKC by assessing the effects of the thiazolid inedione insulin-sensitizer BRL-49653 on PKC isoenzymes in muscle. BRL -49653 increased the recovery of nPKC isoenzymes in cytosolic fraction s of red muscle from fat-fed rats, reducing their apparent activation and/or downregulation, whereas PKC in control rats was unaffected. Bec ause BRL-49653 also improves insulin-stimulated glucose uptake in fat- fed rats and reduces muscle lipid storage, especially diglyceride cont ent, these results strengthen the association between lipid availabili ty, nPKC activation, and skeletal muscle insulin resistance and suppor t the hypothesis that chronic activation of nPKC isoenzymes is involve d in the generation of muscle insulin resistance in fat-fed rats.