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7163638 
Journal Article 
PKC delta is activated in the liver of obese Zucker rats and mediates diet-induced whole body insulin resistance and hepatocyte cellular insulin resistance 
Greene, MW; Burrington, CM; Luo, Y; Ruhoff, MS; Lynch, DT; Chaithongdi, N; , 
2014 
1 
Journal of Nutritional Biochemistry
ISSN: 0955-2863
EISSN: 1873-4847 
ELSEVIER SCIENCE INC 
NEW YORK 
281-288 
24524901 
WOS:000331683700003 
Insulin resistance can arise when pathological levels of free fatty acids (FFAs) and proinflammatory cytokines disrupt insulin signaling. Protein kinase C delta (PKC delta) is a FFA- and a proinflammatory cytokine-regulated protein kinase that is associated with inhibition of insulin signaling and action. To gain insight into the role of PKC delta in insulin resistance, PKC delta activation was studied in a genetic model of obesity-linked insulin resistance. PKC delta was found to be activated in the liver of obese insulin-resistant Zucker rats and in isolated cultured hepatocytes. PKC delta was further studied in PKC delta-null mice and their wild-type littermates fed a high-fat or control diet for 10 weeks. PKC delta-null mice on a high-fat diet had improved insulin sensitivity and hepatic insulin signaling compared to wild-type littermates. Additionally, the deleterious effect of a high-fat diet on glucose tolerance in wild-type mice was completely blocked in PKC delta-null mice. To directly test the role of PKC delta in cellular insulin resistance, primary hepatocytes from the high-fat diet mice were isolated and stimulated with insulin. Primary hepatocytes from PKC delta-null mice had improved insulin-stimulated Akt and FOXO phosphorylation compared to hepatocytes from wild-type littermates. Consistent with this result, tumor necrosis factor alpha-mediated inhibition of insulin signaling was blocked in PKC delta knockdown primary hepatocytes. These results indicate that PKC delta plays a role in insulin resistance and is consistent with the hypothesis that PKC delta is a negative regulator of insulin signaling and thus may be a therapeutic target for the treatment of type 2 diabetes. (C) 2014 Elsevier Inc. All rights reserved.