Dataset Information

Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice.

ABSTRACT:

Background

Obesity 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.

Methods

Gene 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.

Results

Obese 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-1?, IL1RN, TNF-? and TGF?-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.

Conclusions

Macrophage 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.

SUBMITTER: Stanton MC

PROVIDER: S-EPMC3070617 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Publications

Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice.

Stanton Michaela C MC Chen Shu-Cheng SC Jackson James V JV Rojas-Triana Alberto A Kinsley David D Cui Long L Fine Jay S JS Greenfeder Scott S Bober Loretta A LA Jenh Chung-Her CH

Journal of inflammation (London, England) 20110316

<h4>Background</h4>Obesity 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.<h4>Methods</h4>Gene expression analysis in multiple organs from obese mice was done wi ...[more]

PMID: 21410952

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Project description:OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here, we aimed to investigate the interaction between adipose tissue and liver in NAFLD and identify potential early plasma markers that predict nonalcoholic steatohepatitis (NASH). RESEARCH DESIGN AND METHODS: C57Bl/6 mice were chronically fed a high-fat diet to induce NAFLD and compared with mice fed a low-fat diet. Extensive histological and phenotypical analyses coupled with a time course study of plasma proteins using multiplex assay were performed. RESULTS: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into four subgroups: low-fat low (LFL) responders displaying normal liver morphology, low-fat high (LFH) responders showing benign hepatic steatosis, high-fat low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and high fat high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared with HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodeling. Plasma haptoglobin, IL-1?, TIMP-1, adiponectin, and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin, and MIP-1? early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1?, MIP-1?, and MIP-2, whereas insulin, TIMP-1, granulocyte chemotactic protein 2, and myeloperoxidase emerged as late markers. CONCLUSIONS: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH.

Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.

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Dataset Information

Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice.

Background

Methods

Results

Conclusions

Publications

Inflammatory Signals shift from adipose to liver during high fat feeding and influence the development of steatohepatitis in mice.

Similar Datasets

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