Epigenomic derangement of hepatic glucose metabolism by feeding of high fructose diet and its prevention by Rosiglitazone in rats

Background. The high consumption of fructose leads to the increasing incidence of insulin resistance by several unknown mechanisms. Hepatic glucose metabolism may also be an important target of fructose-induced-metabolic alterations. Aim. The aim of present study was to investigate alterations in hepatic glycogenolysis, glycogenesis and gluconeogenic fluxes by feeding of 21% high fructose diet and the effects of Rosiglitazone treatment to prevent these derangements in rats. Methods. Rats were maintained on normal chow and high fructose diet with or without Rosiglitazone for 8 weeks and various biochemical and gene expression measures were estimated. Results. The feeding of high fructose diet impaired glucose, insulin and pyruvate tolerance tests and increased blood HbA(1c), insulin, triglyceride, free fatty acids and homeostasis model assessment after 8 weeks. In addition, high fructose diet feeding increased expression of phosphoenol-pyruvatecorboxykinase, glucose-6-phosphatase, sterol regulatory element binding proteins-1 and fatty acid synthase through enhanced expression of fork-head receptor, peroxisome proliferator activated receptor-gamma-co-activator 1 and cAMP reactive element binding protein. The treatment with Rosiglitazone inhibited all these derangements, i.e. hepato-lipogenic and gluconeogenic effects of high fructose diet feeding in rats. Conclusions. Together these findings suggest that high fructose diet induced hepatic gluconeogenic and lipogenic rate, and increased circulating triglycerides and free fatty acids, which may be the major risk factors for glucose intolerance, hyperglycemia and insulin resistance in rats. In such situations high fructose flux also induces transcriptional cascade of gluconeogenic enzymes through the modulation of various associated transcriptional factors. (C) 2008 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.