title: 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.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.forename: Thijs Willem Hendrik
authors.initials: TW
authors.lastname: Pols
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Nomura
authors.forename: Sokrates
authors.initials: S
authors.lastname: Stein
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007333:Insulin Resistance / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D018925:Chemokines; C513561:Gpbar1 protein, mouse; D008070:Lipopolysaccharides; D046912:Multiprotein Complexes; D043562:Receptors, G-Protein-Coupled; C546843:mTOR protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases