• Clare M Reynolds, Fiona C McGillicuddy, Karen A Harford, Orla M Finucane, Kingston H G Mills, and Helen M Roche.
• Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
• Mol Nutr Food Res. 2012 Aug 1; 56 (8): 1212-22.

ScopeInflammasome-mediated inflammation is a critical regulator of obesity-induced insulin resistance (IR). We hypothesized that saturated fatty acids (SFA) directly prime the NLRP3 inflammasome via TLR4 concurrent with IR. We focused on dendritic cells (DCs) (CD11c(+) CD11b(+) F4/80(-) ), which are recruited into obese adipose tissue following high-fat diet (HFD) challenge and are a key cell in inflammasome biology.Methods And ResultsC57BL/6 mice were fed HFD for 16 weeks (45% kcal palm oil), glucose homeostasis was monitored by glucose and insulin tolerance tests. Stromal vascular fraction (SVF) cells were isolated from adipose and analyzed for CD11c(+) CD11b(+) F480(-) DC. Following coculture with bone marrow derived DC (BMDC) insulin-stimulated (3) H-glucose transport into adipocytes, IL-1β secretion and caspase-1 activation was monitored. BMDCs primed with LPS (100 ng/mL), linoleic acid (LA; 200 μM), or palmitic acid (PA; 200 μM) were used to monitor inflammasome activation. We demonstrated significant infiltration of DCs into adipose after HFD. HFD-derived DCs reduce adipocyte insulin sensitivity upon coculture co-incident with enhanced adipocyte caspase-1 activation/IL-1β secretion. HFD-derived DCs are skewed toward a pro-inflammatory phenotype with increased IL-1β secretion, IL-1R1, TLR4, and caspase-1 expression. Complementary in vitro experiments demonstrate that TLR4 is critical in propagating SFA-mediated inflammasome activation.ConclusionSFA represent metabolic triggers priming the inflammasome, promoting adipocyte inflammation/IR, suggesting direct effects of SFA on inflammasome activation via TLR4.© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

36 keywords...

hide…