Reduction of obesity-associated white adipose tissue inflammation by rosiglitazone is associated with reduced non-alcoholic fatty liver disease in LDLr-deficient mice.

Petra Mulder,Teake Kooistra,Lars Verschuren,Martine C Morrison,Peter Y Wielinga,J Hajo Van Bockel,Robert Kleemann,Wen Liang

doi:10.1038/srep31542

Abstract

Obesity is associated with chronic low-grade inflammation that drives the development of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). We recently showed that white adipose tissue (WAT) constitutes an important source of inflammatory factors. Hence, interventions that attenuate WAT inflammation may reduce NAFLD development. Male LDLr−/− mice were fed a high-fat diet (HFD) for 9 weeks followed by 7 weeks of HFD with or without rosiglitazone. Effects on WAT inflammation and NAFLD development were analyzed using biochemical and (immuno)histochemical techniques, combined with gene expression analyses. Nine weeks of HFD feeding induced obesity and WAT inflammation, which progressed gradually until the end of the study. Rosiglitazone fully blocked progression of WAT inflammation and activated PPARγ significantly in WAT. Rosiglitazone intervention did not activate PPARγ in liver, but improved liver histology and counteracted the expression of genes associated with severe NAFLD in humans. Rosiglitazone reduced expression of pro-inflammatory factors in WAT (TNF-α, leptin) and increased expression of adiponectin, which was reflected in plasma. Furthermore, rosiglitazone lowered circulating levels of pro-inflammatory saturated fatty acids. Together, these observations provide a rationale for the observed indirect hepatoprotective effects and suggest that WAT represents a promising therapeutic target for the treatment of obesity-associated NAFLD.

Highlights

A strong increase in CLS is observed at the time point at which a white adipose tissue (WAT) depot has reached its maximal mass as shown very recently in a model of diet-induced obesity[5]
After 16 weeks, CLS formation was most pronounced in epididymal WAT (Fig. 1A), while CLS were hardly observed in mesenteric WAT and inguinal WAT
peroxisome proliferator-activated receptor-γ (PPARγ) with reported anti-inflammatory properties[14,15,16], as a model compound to intervene in manifest WAT inflammation

Summary

Introduction

A strong increase in CLS is observed at the time point at which a WAT depot has reached its maximal mass as shown very recently in a model of diet-induced obesity[5]. In addition to the increased fat flux, inflamed WAT may produce inflammatory factors that can contribute to systemic inflammation and promote the progression from liver steatosis to non-alcoholic steatohepatitis (NASH)[2,11,12]. We have shown that surgical removal of inflamed abdominal (epididymal) WAT in mice reduced lobular inflammation and attenuated NASH development[5], suggesting that WAT constitutes an possible target for the treatment of NASH. We investigated whether rosiglitazone intervention can reduce manifest WAT inflammation and would attenuate subsequent NAFLD development. We first determined the time point at which WAT inflammation develops during high-fat diet treatment in LDLr−/− mice. We studied the therapeutic effect of rosiglitazone on WAT inflammation and associated NAFLD development

Methods

Results

Conclusion