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.
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.
Nguyen
M T Audrey
MT
Division of Endocrinology-Metabolism, University of California, San Diego, La Jolla, California 92093, USA. m9nguyen@ucsd.edu
Favelyukis
Svetlana
S
Nguyen
Anh-Khoi
AK
Reichart
Donna
D
Scott
Peter A
PA
Jenn
Alan
A
Liu-Bryan
Ru
R
Glass
Christopher K
CK
Neels
Jaap G
JG
Olefsky
Jerrold M
JM
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D039481:CD11b Antigen / Q000096:biosynthesis; D039521:CD11c Antigen / Q000096:biosynthesis; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D007249:Inflammation; D007333:Insulin Resistance; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D039481:CD11b Antigen; D039521:CD11c Antigen; D005230:Fatty Acids, Nonesterified; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4