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J. Biol. Chem., Vol. 283, Issue 33, 22620-22627, August 15, 2008

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Peroxisome Proliferator-activated Receptor Activation Promotes Infiltration of Alternatively Activated Macrophages into Adipose Tissue^*

Rinke Stienstra¹, Caroline Duval, Shohreh Keshtkar, Jeroen van der Laak^¶, Sander Kersten, and Michael Müller²

From the Nutrition, Metabolism, and Genomics Group, Division of Human Nutrition, Wageningen University, 6700 EV Wageningen, Nutrigenomics Consortium, Top Institute of Food and Nutrition, Wageningen, and ^¶Department of Pathology, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands

Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators, including tumor necrosis factor and interleukin-6 (IL-6). Recent data suggest that during diet-induced obesity the phenotype of adipose-resident macrophages changes from alternatively activated macrophages toward a more classical and pro-inflammatory phenotype. Here, we explore the effect of peroxisome proliferator-activated receptor activation on obesity-induced inflammation in 129SV mice fed a high fat diet for 20 weeks. High fat feeding increased bodyweight gain, adipose tissue mass, and liver triglycerides. Rosiglitazone treatment further increased adipose mass, reduced liver triglycerides, and changed adipose tissue morphology toward smaller adipocytes. Surprisingly, rosiglitazone markedly increased the number of macrophages in adipose tissue, as shown by immunohistochemical analysis and quantification of macrophage marker genes CD68 and F4/80+. In adipose tissue, markers for classically activated macrophages including IL-18 were down-regulated, whereas markers characteristic for alternatively activated macrophages (arginase 1, IL-10) were up-regulated by rosiglitazone. Importantly, conditioned media from rosiglitazone-treated alternatively activated macrophages neutralized the inhibitory effect of macrophages on 3T3-L1 adipocyte differentiation, suggesting that alternatively activated macrophages may be involved in mediating the effects of rosiglitazone on adipose tissue morphology and mass. Our results suggest that short term rosiglitazone treatment increases infiltration of alternatively activated macrophages in adipose tissue. The alternatively activated macrophages might play a role in peroxisome proliferator-activated receptor-dependent expansion and remodeling of adipose tissue.

Received for publication, December 19, 2007 , and in revised form, May 26, 2008.

^* This study was supported by the Centre for Human Nutrigenomics and Top Institute of Food and Nutrition. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Dept. of Internal Medicine, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, The Netherlands.

² To whom correspondence should be addressed: Division of Human Nutrition, Wageningen University, P. O. Box 8129, 6700 EV Wageningen, The Netherlands, Tel.: 31-317-482590; Fax: 31-317-483342; E-mail: michael.muller{at}wur.nl.

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