Abstract
BackgroundObesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Molecular mechanisms underlying inflammatory events during high fat diet-induced obesity are poorly defined in mouse models of obesity. This work investigated gene activation signals integral to the temporal development of obesity.MethodsGene expression analysis in multiple organs from obese mice was done with Taqman Low Density Array (TLDA) using a panel of 92 genes representing cell markers, cytokines, chemokines, metabolic, and activation genes. Mice were monitored for systemic changes characteristic of the disease, including hyperinsulinemia, body weight, and liver enzymes. Liver steatosis and fibrosis as well as cellular infiltrates in liver and adipose tissues were analyzed by histology and immunohistochemistry.ResultsObese C57BL/6 mice were fed with high fat and cholesterol diet (HFC) for 6, 16 and 26 weeks. Here we report that the mRNA levels of macrophage and inflammation associated genes were strongly upregulated at different time points in adipose tissues (6-16 weeks) and liver (16-26 weeks), after the start of HFC feeding. CD11b+ and CD11c+ macrophages highly infiltrated HFC liver at 16 and 26 weeks. We found clear evidence that signals for IL-1β, IL1RN, TNF-α and TGFβ-1 are present in both adipose and liver tissues and that these are linked to the development of inflammation and insulin resistance in the HFC-fed mice.ConclusionsMacrophage infiltration accompanied by severe inflammation and metabolic changes occurred in both adipose and liver tissues with a temporal shift in these signals depending upon the duration of HFC feeding. The evidences of gene expression profile, elevated serum alanine aminotransferase, and histological data support a progression towards nonalcoholic fatty liver disease and steatohepatitis in these HFC-fed mice within the time frame of 26 weeks.
Highlights
Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease
Up to 30 percent of the general population is affected by nonalcoholic fatty liver disease (NAFLD) with 35 to 50 percent of obese adults being diagnosed with nonalcoholic steatohepatitis (NASH)
In order to minimize variability in our gene analysis results, mice were selected for their susceptibility to diet-induced obesity at day 21 following the start of high fat and cholesterol (HFC) feeding
Summary
Obesity and inflammation are highly integrated processes in the pathogenesis of insulin resistance, diabetes, dyslipidemia, and non-alcoholic fatty liver disease. Increased adiposity with the consequence of chronic lowgrade inflammation and insulin resistance or type 2 diabetes has been linked to the development of nonalcoholic fatty liver disease (NAFLD). There are a number of observations in the literature linking adiposity with inflammation and increased liver disease. In insulin-resistant patients with fatty liver disease, there is a significant upregulation of genes involved in fatty acid partitioning and binding proteins, monocyte recruitment and inflammation [3]. Obese mice demonstrate a significant increase in plasminogen activator in the fatty liver [4]. The absence of CCR2 protects the liver against fat accumulation in the diet-induced obese mouse [5]
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