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Mol Nutr Food Res. 2012 Aug;56(8):1212-22. doi: 10.1002/mnfr.201200058. Epub 2012 Jun 15.

Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance.

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  • 1Nutrigenomics Research Group, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.

Abstract

SCOPE:

Inflammasome-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 RESULTS:

C57BL/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.

CONCLUSION:

SFA represent metabolic triggers priming the inflammasome, promoting adipocyte inflammation/IR, suggesting direct effects of SFA on inflammasome activation via TLR4.

PMID:
22700321
DOI:
10.1002/mnfr.201200058
[PubMed - indexed for MEDLINE]
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