title: PKCδ is activated in the liver of obese Zucker rats and mediates diet-induced whole body insulin resistance and hepatocyte cellular insulin resistance.
abstract: Insulin resistance can arise when pathological levels of free fatty acids (FFAs) and proinflammatory cytokines disrupt insulin signaling. Protein kinase C delta (PKCδ) 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 PKCδ in insulin resistance, PKCδ activation was studied in a genetic model of obesity-linked insulin resistance. PKCδ was found to be activated in the liver of obese insulin-resistant Zucker rats and in isolated cultured hepatocytes. PKCδ was further studied in PKCδ-null mice and their wild-type littermates fed a high-fat or control diet for 10 weeks. PKCδ-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 PKCδ-null mice. To directly test the role of PKCδ in cellular insulin resistance, primary hepatocytes from the high-fat diet mice were isolated and stimulated with insulin. Primary hepatocytes from PKCδ-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 PKCδ knockdown primary hepatocytes. These results indicate that PKCδ plays a role in insulin resistance and is consistent with the hypothesis that PKCδ is a negative regulator of insulin signaling and thus may be a therapeutic target for the treatment of type 2 diabetes.
authors: Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA; College of Human Sciences, Auburn University, Auburn, AL 36849, USA; Bassett Research Institute, Bassett Healthcare Network, Cooperstown, NY, USA. Electronic address: mwgreene@auburn.edu.
authors: Michael W
authors: MW
authors: Greene
authors: Bassett Research Institute, Bassett Healthcare Network, Cooperstown, NY, USA.
authors: Christine M
authors: CM
authors: Burrington
authors: College of Human Sciences, Auburn University, Auburn, AL 36849, USA.
authors: Yuwen
authors: Y
authors: Luo
authors: Bassett Research Institute, Bassett Healthcare Network, Cooperstown, NY, USA.
authors: Mary S
authors: MS
authors: Ruhoff
authors: Bassett Research Institute, Bassett Healthcare Network, Cooperstown, NY, USA.
authors: Darin T
authors: DT
authors: Lynch
authors: Department of Internal Medicine, Bassett Medical Center, Bassett Healthcare Network, Cooperstown, NY, USA.
authors: Niyutchai
authors: N
authors: Chaithongdi
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology*; D008297:Male; D009765:Obesity / Q000201:enzymology / Q000378:metabolism*; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker
chemical_list: D051745:Protein Kinase C-delta
keywords: Hepatocyte; Insulin; Protein kinase C