title: Macrophage TCF-4 co-activates p65 to potentiate chronic inflammation and insulin resistance in mice.
abstract: Transcription factor 4 (TCF-4) was recently identified as a candidate gene for the cause of type 2 diabetes, although the mechanisms have not been fully elucidated. In the present study, we demonstrated that the TCF-4 transgene in macrophages aggravated high-fat diet (HFD)-induced insulin resistance and chronic inflammation, characterized by the elevation of proinflammatory cytokines in the blood, liver and white adipose tissue, as well as a proinflammatory profile of immune cells in visceral fats in mice. Mechanistically, TCF-4 functioned as a co-activator of p65 to amplify the saturated free fatty acid (FFA)-stimulated promoter activity, mRNA transcription and secretion of proinflammatory cytokines in primary macrophages. Blockage of p65 with a specific interfering RNA or inhibitor could prevent TCF-4-enhanced expression of proinflammatory cytokines in FFA/lipopolysaccharide-treated primary macrophages. The p65 inhibitor could abolish macrophage TCF-4 transgene-aggravated systemic inflammation, glucose intolerance and insulin resistance in HFD-treated mice. In addition, we demonstrated that the mRNA expression of TCF-4 in the peripheral blood monocytes from humans was positively correlated to the levels of interleukin (IL)-1β, tumour necrosis factor α, IL-6 and fasting plasma glucose. In summary, we identified TCF-4 as a co-activator of p65 in the potentiation of proinflammatory cytokine production in macrophages and aggravation of HFD-induced chronic inflammation and insulin resistance in mice.
authors.affiliation: Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Kang
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Along
authors.initials: A
authors.lastname: Hou
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China.
authors.forename: Da
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Orthopaedics, Chengdu Military General Hospital, 270 Rongdu Avenue, Jinniu District, Chengdu, Sichuan 610083, China hongmingmiao@sina.com zhengweipaper@sina.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing 400038, China hongmingmiao@sina.com zhengweipaper@sina.com.
authors.forename: Hongming
authors.initials: H
authors.lastname: Miao
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000502:physiology*; D002478:Cells, Cultured; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis; D059305:Diet, High-Fat; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007333:Insulin Resistance; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000073940:Transcription Factor 4; D051996:Transcription Factor RelA / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D016207:Cytokines; D008070:Lipopolysaccharides; C498144:Rela protein, mouse; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051996:Transcription Factor RelA
keywords: TCF-4; chronic inflammation; insulin resistance; macrophages; p65