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Papers In Press, published online ahead of print October 4, 2007
Medicine, University of California, San Diego, La Jolla, CA 92122
Corresponding Author: m9nguyen{at}ucsd.edu
besity 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 FFAs’ proinflammatory signals. We also demonstrate that F4/80+CD11b+CD11c+ bone marrow derived dendritic cells (BMDCs) have heightened proinflammatory activity compared to F4/80+CD11b+CD11c- BM derived macrophages (BMDMs), and that the proinflammatory activity and JNK phosphorylation of BMDCs, but not BMDMs, 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 WT mice a high fat diet (HFD) for 1 and 12 weeks. AT F4/80+CD11b+CD11c+ cells express increased inflammatory markers compared to 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 HFD-fed mice and that conditioned medium from FFA-treated WT 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.
J. Biol. Chem, 10.1074/jbc.M706762200
Submitted on August 14, 2007
Accepted on October 4, 2007
A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by FFAS via TLR2, TLR4 and JNK-dependent pathways
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