TGR5 reduces macrophage migration through mTOR-induced C/EBPβ differential translation
Alessia Perino, Thijs Willem Hendrik Pols, Mitsunori Nomura, Sokrates Stein, Roberto Pellicciari, Kristina Schoonjans
Alessia Perino, Thijs Willem Hendrik Pols, Mitsunori Nomura, Sokrates Stein, Roberto Pellicciari, Kristina Schoonjans
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Research Article Immunology

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

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 1

Tgr5bm–/– mice display impaired insulin responsiveness.

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Tgr5bm–/– mice display impaired insulin responsiveness. (A) Body weight ...
(A) Body weight curves of Tgr5bm+/+ and Tgr5bm–/– mice fed HFD for 18 weeks. n = 12 per group. (B) Body composition (fat and lean mass) of Tgr5bm+/+ and Tgr5bm–/– mice, determined by EchoMRI. n = 12 per group. (C) Left: Blood glucose levels during ITT (insulin; 0.5 U/kg) in Tgr5bm+/+ and Tgr5bm–/– mice fed HFD for 16 weeks. Right: Average area under the curve (AUC). n = 12 per group. (D) Left: Plasma insulin levels during OGTT in Tgr5bm+/+ and Tgr5bm–/– mice fed HFD for 14 weeks. Right: Average AUC. n = 12 per group. (E) Left: Blood glucose levels during OGTT in Tgr5bm+/+ and Tgr5bm–/– mice fed HFD. Right: AUC. n = 12 per group. (F) HOMA-IR of HFD-fed Tgr5bm+/+ and Tgr5bm–/– mice. n = 12 per group. (G–I) Western blot of phospho-AKT (P-AKT, Ser473), total AKT, and HSP90 in (G) liver, (H) gastrocnemius muscle, and (I) eWAT of HFD-fed Tgr5bm+/+ and Tgr5bm–/– mice injected i.p. with vehicle or insulin (1 U/kg; 10 min). Quantitative densitometry of Western blots is also shown. n = 6 per group. Results represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. genotype; #P < 0.001 vs. control, 2-tailed Student’s t test or 1- or 2-way ANOVA with Bonferroni post-hoc analysis as appropriate.