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Diabetes 54:3458-3465, 2005
© 2005 by the American Diabetes Association, Inc.

Free Fatty Acids Produce Insulin Resistance and Activate the Proinflammatory Nuclear Factor-{kappa}B Pathway in Rat Liver

Guenther Boden1, Pengxiang She1, Maria Mozzoli1, Peter Cheung1, Kiranmai Gumireddy2, Prekumar Reddy2, Xiaqin Xiang3, Zhijan Luo3, and Neil Ruderman3

1 Division of Endocrinology, Diabetes, and Metabolism, Temple University School of Medicine, Philadelphia, Pennsylvania
2 Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, Pennsylvania
3 Diabetes and Metabolism Research Unit, Boston University, Boston, Massachusetts

To study mechanisms by which free fatty acids (FFAs) cause hepatic insulin resistance, we have used euglycemic-hyperinsulinemic clamping with and without infusion of lipid/heparin (to raise or to lower plasma FFAs) in alert male rats. FFA-induced hepatic insulin resistance was associated with increased hepatic diacylglycerol content (+210%), increased activities of two serine/threonine kinases (protein kinase C-{delta} and inhibitor of {kappa}B [I{kappa}B] kinase-ß), increased activation of the proinflammatory nuclear factor-{kappa}B (NF-{kappa}B) pathway (I{kappa}B kinase-ß, +640%; I{kappa}B-{alpha}, –54%; and NF-{kappa}B, +73%), and increased expression of inflammatory cytokines (tumor necrosis factor-{alpha}, +1,700% and interleukin-1ß, +440%) and plasma levels of monocyte chemoattractant protein-1 (+220%). We conclude that FFAs caused hepatic insulin resistance, which can produce overproduction of glucose and hyperglycemia, and initiated inflammatory processes in the liver that could potentially result in the development of steatohepatitis.

Address correspondence to Guenther Boden, MD, Temple University Hospital, 3401 North Broad St., Philadelphia, PA 19140. E-mail: bodengh{at}tuhs.temple.edu

Abbreviations: AMPK, AMP kinase; DAG, diacylglycerol; EGP, endogenous glucose production; FFA, free fatty acid; GIR, glucose infusion rate; I{kappa}B, inhibitor of {kappa}B; IL, interleukin; IRS, insulin receptor substrate; MCP, monocyte chemoattractant protein; NF-{kappa}B, nuclear factor-{kappa}B; PKC, protein kinase C; ROS, reactive oxygen species; TNF, tumor necrosis factor


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