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TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation
Alessia Perino, … , Roberto Pellicciari, Kristina Schoonjans
Alessia Perino, … , Roberto Pellicciari, Kristina Schoonjans
Published November 3, 2014
Citation Information: J Clin Invest. 2014;124(12):5424-5436. https://doi.org/10.1172/JCI76289.
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Research Article Immunology Article has an altmetric score of 48

TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation

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Abstract

The bile acid–responsive G protein–coupled receptor TGR5 is involved in several metabolic processes, and recent studies suggest that TGR5 activation may promote pathways that are protective against diet-induced diabetes. Here, we investigated the role of macrophage-specific TGR5 signaling in protecting adipose tissue from inflammation and associated insulin resistance. Examination of adipose tissue from obese mice lacking macrophage Tgr5 revealed enhanced inflammation, increased chemokine expression, and higher macrophage numbers compared with control obese animals. Moreover, macrophage-specific deletion of Tgr5 exacerbated insulin resistance in obese animals. Conversely, pharmacological activation of TGR5 markedly decreased LPS-induced chemokine expression in primary macrophages. This reduction was mediated by AKT-dependent activation of mTOR complex 1, which in turn induced the differential translation of the dominant-negative C/EBPβ isoform, liver inhibitory protein (LIP). Overall, these studies reveal a signaling pathway downstream of TGR5 that modulates chemokine expression in response to high-fat diet and suggest that targeting this pathway has the potential to be therapeutically exploited for prevention of chronic inflammatory diseases and type 2 diabetes mellitus.

Authors

Alessia Perino, Thijs Willem Hendrik Pols, Mitsunori Nomura, Sokrates Stein, Roberto Pellicciari, Kristina Schoonjans

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Figure 4

Exacerbated adipose tissue inflammation in LysM-Cre Tgr5fl/fl mice.

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Exacerbated adipose tissue inflammation in LysM-Cre Tgr5fl/fl mice.
(A) ...
(A) Representative F4/80 staining of eWAT of HFD-fed Tgr5fl/fl and LysM-Cre Tgr5fl/fl mice. Arrows indicate CLS. Scale bars: 50 μm. (B) Quantification of CLS from A (expressed as mean per microscopic field). n = 3 per group. (C) mRNA levels of macrophage markers in eWAT of HFD-fed Tgr5fl/fl and LysM-Cre Tgr5fl/fl mice. n = 12 per group. (D and E) mRNA levels of (D) proinflammatory M1 and (E) antiinflammatory M2 markers in eWAT of HFD-fed Tgr5fl/fl and LysM-Cre Tgr5fl/fl mice. n = 12 per group. Results represent mean ± SEM. *P < 0.05, **P < 0.01 vs. genotype, 2-tailed Student’s t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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