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*

By M. A. Nguyen, S. Favelyukis, Anh-Khoi Nguyen, D. Reichart, P. Scott, A. Jenn, R. Liu-Bryan, Christopher K. Glass, J. Neels, Jerrold M. Olefsky. Journal of Biological Chemistry, 2007

1,034 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Immunology

View Paper: https://www.semanticscholar.org/paper/ad7c3b660a296dccfba7f88af42b016cc38e632e

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Citations in the corpus

Adipose Tissue Dysfunction as Determinant of Obesity-Associated Metabolic Complications (2019, background): “For instance, FFAs can promote inflammation by binding to toll-like receptors 2 and 4 through the adaptor protein fetuin-A, resulting in activation of nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) signaling pathways [104,116].”
Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. (2010, background): “The 2 largest classes of ATMs can be distinguished based on expression of the antigens F4/80, CD11b, and CD11c; one population expresses all 3 antigens (FBC cells) and a second expresses only F4/80 and CD11b (FB cells) (46, 47).”
Macrophage polarization: An opportunity for improved outcomes in biomaterials and regenerative medicine (2012, background): “pathways, suggesting a potential mechanism by which obesityinduced inflammation may occur [73,74].”
The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease (2011, background): “However, as prolonged exercise increases lipolysis and elevates plasma levels of free fatty acids, which are ligands for TLR2 and TLR4 (Ref”
Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment (2011, neutral): “However, their role in the control of glucose metabolism has been demonstrated elsewhere (Macia et al, 2006; Nguyen et al, 2007) by means of the secretion of CXCL14 required for the regulatory role of DC on lymphocytes (Hara & Nakayama, 2009) and for other inﬂammatory diseases such as inﬂammatory”
Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. (2014, background): “Just as adipose tiss e, these skeletal muscle macrophages exhibit a pro-inflammatory M1 phenotype [47] accompanied with an increased expression of inflammatory factors in muscle cells [30, 47] contributing locally to insulin resistance.”