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Peroxisome Proliferator-Activated Receptor Protects against Obesity-Induced Hepatic Inflammation

Nutrition, Metabolism and Genomics Group (R.S., S.M., D.P., S.K., M.M.), Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, The Netherlands; Nutrigenomics Consortium (R.S., S.K., M.M.), Wageningen Center of Food Sciences, 6709 PA Wageningen, The Netherlands; and Department of Pathology (C.M.), Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Michael Müller, Ph.D., Division of Human Nutrition, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands. E-mail: michael.muller{at}wur.nl.

Recently it has become evident that obesity is associated with low-grade chronic inflammation. The transcription factor peroxisome proliferator-activated receptor (PPAR) has been shown to have a strong antiinflammatory action in liver. However, the role of PPAR in obesity-induced inflammation is much less clear. Therefore, the aim of our study was to determine whether PPAR plays a role in obesity-induced hepatic inflammation. To induce obesity, wild-type sv129 and PPAR^–/– mice were exposed to a chronic high-fat diet (HFD), using a low-fat diet (LFD) as control. In wild-type mice, HFD significantly increased the hepatic and adipose expression of numerous genes involved in inflammation. Importantly, this effect was amplified in PPAR^–/– mice, suggesting an antiinflammatory role of PPAR in liver and adipose tissue. Further analysis identified specific chemokines and macrophage markers, including monocyte chemotactic protein 1 and F4/80⁺, that were elevated in liver and adipose tissue of PPAR^–/– mice, indicating increased inflammatory cell recruitment in the knockout animals. When all groups of mice were analyzed together, a significant correlation between hepatic triglycerides and expression of inflammatory markers was observed. Many inflammatory genes that were up-regulated in PPAR^–/– livers by HFD were down-regulated by treatment with the PPAR ligand Wy-14643 under normal nonsteatotic conditions, either in vivo or in vitro, suggesting an antiinflammatory effect of PPAR that is independent of reduction in liver triglycerides. In conclusion, our results suggest that PPAR protects against obesity-induced chronic inflammation in liver by reducing hepatic steatosis, by direct down-regulation of inflammatory genes, and by attenuating inflammation in adipose tissue.

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