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J. Biol. Chem., Vol. 282, Issue 48, 35279-35292, November 30, 2007

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A Subpopulation of Macrophages Infiltrates Hypertrophic Adipose Tissue and Is Activated by Free Fatty Acids via Toll-like Receptors 2 and 4 and JNK-dependent Pathways^*

M. T. Audrey Nguyen¹, Svetlana Favelyukis, Anh-Khoi Nguyen, Donna Reichart, Peter A. Scott^¶, Alan Jenn, Ru Liu-Bryan^¶, Christopher K. Glass, Jaap G. Neels, and Jerrold M. Olefsky

From the Division of Endocrinology-Metabolism, the Department of Cellular and Molecular Medicine, and the ^¶Veterans Affairs Medical Center, University of California, San Diego, La Jolla, California 92093

Obesity and type 2 diabetes are characterized by decreased insulin sensitivity, elevated concentrations of free fatty acids (FFAs), and increased macrophage infiltration in adipose tissue (AT). Here, we show that FFAs can cause activation of RAW264.7 cells primarily via the JNK signaling cascade and that TLR2 and TLR4 are upstream of JNK and help transduce FFA proinflammatory signals. We also demonstrate that F4/80⁺CD11b⁺CD11c⁺ bone marrow-derived dendritic cells (BMDCs) have heightened proinflammatory activity compared with F4/80⁺CD11b⁺CD11c^- bone marrow-derived macrophages and that the proinflammatory activity and JNK phosphorylation of BMDCs, but not bone marrow-derived macrophages, was further increased by FFA treatment. F4/80⁺CD11b⁺CD11c⁺ cells were found in AT, and the proportion and number of these cells in AT is increased in ob/ob mice and by feeding wild type mice a high fat diet for 1 and 12 weeks. AT F4/80⁺CD11b⁺CD11c⁺ cells express increased inflammatory markers compared with F4/80⁺CD11b⁺CD11c^- cells, and FFA treatment increased inflammatory responses in these cells. In addition, we found that CD11c expression is increased in skeletal muscle of high fat diet-fed mice and that conditioned medium from FFA-treated wild type BMDCs, but not TLR2/4 DKO BMDCs, can induce insulin resistance in L6 myotubes. Together our results show that FFAs can activate CD11c⁺ myeloid proinflammatory cells via TLR2/4 and JNK signaling pathways, thereby promoting inflammation and subsequent cellular insulin resistance.

Received for publication, August 14, 2007

^* This work was supported by a University of California Discovery Biostar Grant and National Institutes of Health Grants DK33651 (to J. M. O.) and DK074868 (to C. K. G. and J. M. O.); the Fonds de la Recherche en Santédu Québec (to M. T. A. N.); National Institutes of Health Grant AR049416 (to R. L.-B.); and Scientist Development Grant 0635408N from the American Heart Association (to J. G. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ To whom correspondance should be addressed: University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0673. Fax: 858-534-6653; E-mail: m9nguyen{at}ucsd.edu.

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