Identification of a Major Defect in Insulin-Resistant Tissues of Genetically Obese (fa/fa) Rats: Impaired Protein Kinase C

Abstract

In perfused lean rat hearts, the activator of protein kinase C phorbol myristate acetate (PMA), when present alone, stimulates glucose transport but inhibits the insulin stimulation of this transport. PMA also inactivates glycogen synthase in hepatocytes. In contrast, none of these effects are observed in hearts and hepatocytes of obese animals, indicating an impaired protein kinase C activation in these tissues, which are insulin resistant. Direct measurements of protein kinase C activity in lean rat hearts revealed that PMA provokes a translocation of the enzyme from a soluble to a particulate fraction. In obese rat hearts, the basal distribution of protein kinase C is altered (more activity is found in the soluble and less in the particulate fraction), and the translocation induced by PMA is impaired. Pretreatment of lean rats with PMA in vivo, aimed at downregulating protein kinase C, induces the same defects (i.e., insulin resistance and unresponsiveness to PMA) as those observed in hearts of untreated obese animals. The results indicate that part of the insulin resistance might be the consequence of altered modulation of insulin action by protein kinase C.

Impaired glucose metabolism in the heart of obese Zucker rats after treatment with phorbol ester

“…They further demonstrate that the diminished activation of PKCa observed in the heart of obese Zucker rats is associated with complete suppression of GLUT-4 activation. Our results are in agreement with an earlier study of Van der Werve et al 11 showing that myocardial PKC activation by phorbol ester is impaired in obese Zucker rats when compared to that of lean animals. Hearts were perfused according to the Langendorff method with EE-buffer for an equilibration period of 60 min.…”

“…18 Moreover, activation of PKC is suggested to be involved in the regulation of proteins controlling glucose oxidation 19 and glycogen metabolism. 11,20 However, at the present time there is scant information linking the myocardial metabolism of glucose to the activation of the PKC signaling pathway. Therefore, we investigated whether PKC is involved in the regulation of the cardiac glucose metabolism and whether obesity influences this regulation.…”

“…5,6 Obese Zucker rats also exhibit diminished glucose uptake, glucose oxidation 7 and incorporation of glucose into glycogen 8 as well as differences in protein turnover and amino acid metabolism. 9 Moreover, in the obese Zucker rat expression of protein kinase C (PKC) in soleus muscle 10 as well as activation of PKC in response to hormones or phorbol esters, was found to be diminished in the heart 11 and in hepatocytes 12,13 when compared to lean rats.…”

“…This kinase family has also been shown to be involved in the translocation of glucose transporters (GLUT) and=or regulation of glucose uptake in the heart 11 and skeletal muscle cells 16,17 and adipocytes. 18 Moreover, activation of PKC is suggested to be involved in the regulation of proteins controlling glucose oxidation 19 and glycogen metabolism.…”

Alterations in insulin-induced postreceptor signaling in adipocytes of the Otsuka Long-Evans Tokushima fatty rat strain

“…Previous reports of impaired PKC activity from obese Zucker rats heart and liver and a decrease in the responsiveness of glucose uptake to insulin and TPA in Zucker and old-obese rats (Ishizuka et al 1993, Van de Werve et al 1987 prompted us to investigate PKC immunoreactivity and PKC activity in OLETF rats.…”