Abstract
Objective
Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance.
Subjects and results
Wild-type (WT) and Mrp14−/− mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14−/− mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14−/− macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14−/− macrophages.
Conclusion
Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.
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Funding
This work was supported by grants from National Institutes of Health (K01DK105108 and K99ES026241), National Natural Science Foundation of China (81670431, 31870906, 81370942, Y2110580, and 81101247), National Science and Technology Major Project (2016YFC1305803), American Heart Association (17GRNT33670485), American Association of Immunologists (CIIF-8745), and Hubei Regenerative Medicine Research Center.
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CX and JZ researched data and wrote the paper. XR and ZB researched data. MR, ZB, SZ, DIS, SR, HM, ACT, and XR contributed to discussion. JZ, ZB, MR, ACT, and SZ reviewed and edited the paper. JZ is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
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Xia, C., Razavi, M., Rao, X. et al. MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance. Int J Obes 43, 2434–2447 (2019). https://doi.org/10.1038/s41366-019-0366-4
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DOI: https://doi.org/10.1038/s41366-019-0366-4
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