Abstract

Obesity is known to result in insulin resistance, Type 2 diabetes and the eventual development of non-alcoholic steatohepatitis (NASH). The underlying molecular mechanisms involved in the progression of these diseases are currently unknown. To obtain a better understanding of these molecular pathways, DNA microarray analysis was used to examine gene expression profiles during the development of diet-induced obesity (DIO) in the mouse. Mice fed a high fat diet (HFD) quickly become obese primarily due to fat deposition, resulting in a significant increase in body weight and marked hyperinsulinemia in comparison to chow fed (ND) controls. Hepatic gene expression profiles were examined using trend and correlation analysis in HFD and ND groups at 0, 2, 4, 8 and 12 weeks after high fat feeding. Statistical analysis using ANOVA identified 1947 genes to have a significant diet effect ( P < 0.05). Analysis of the data revealed significant changes in gene expression in genes involved in protective mechanisms in the early weeks of HFD such as those in glycolysis and beta-oxidation. At the later time points there was down regulation of gene expression in pathways of leptin signaling, liver regeneration and protective radical scavengers. In addition, expression of genes involved in gluconeogenesis and fat synthesis pathways were also more highly expressed at the later time points. This microarray analysis has identified several novel pathways that are involved in the development of insulin resistance and steatosis in the liver.