title: HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance.
abstract: Proinflammatory cytokines play important roles in insulin resistance. Here we report that mice with a T-cell-specific conditional knockout of HGK (T-HGK cKO) develop systemic inflammation and insulin resistance. This condition is ameliorated by either IL-6 or IL-17 neutralization. HGK directly phosphorylates TRAF2, leading to its lysosomal degradation and subsequent inhibition of IL-6 production. IL-6-overproducing HGK-deficient T cells accumulate in adipose tissue and further differentiate into IL-6/IL-17 double-positive cells. Moreover, CCL20 neutralization or CCR6 deficiency reduces the Th17 population or insulin resistance in T-HGK cKO mice. In addition, leptin receptor deficiency in T cells inhibits Th17 differentiation and improves the insulin sensitivity in T-HGK cKO mice, which suggests that leptin cooperates with IL-6 to promote Th17 differentiation. Thus, HGK deficiency induces TRAF2/IL-6 upregulation, leading to IL-6/leptin-induced Th17 differentiation in adipose tissue and subsequent insulin resistance. These findings provide insight into the reciprocal regulation between the immune system and the metabolism.
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Huai-Chia
authors.initials: HC
authors.lastname: Chuang
authors.affiliation: 1] Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, 160, Sec. 3, Chung-Kang Road, Taichung 40705, Taiwan [2] Faculty of Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
authors.forename: Wayne H-H
authors.initials: WH
authors.lastname: Sheu
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Yu-Jhen
authors.initials: YJ
authors.lastname: Cheng
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Pau-Yi
authors.initials: PY
authors.lastname: Huang
authors.affiliation: Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
authors.forename: Ju-Pi
authors.initials: JP
authors.lastname: Li
authors.affiliation: Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, 160, Sec. 3, Chung-Kang Road, Taichung 40705, Taiwan.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Chiu
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: UT Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Faculty of Medicine, British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London, South Kensington Campus, London SW7 2AZ, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.affiliation: 1] Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Tse-Hua
authors.initials: TH
authors.lastname: Tan
mesh_terms: D016475:3T3 Cells; D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D002454:Cell Differentiation; D005091:Exons; D005347:Fibroblasts / Q000378:metabolism; D005951:Glucose Tolerance Test; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D019169:Jurkat Cells; D008214:Lymphocytes / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism*; D058504:Th17 Cells / Q000166:cytology*; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D017252:CD3 Complex; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D054411:Receptors, Leptin; D047992:TNF Receptor-Associated Factor 2; D000097782:NF-kappaB-Inducing Kinase; C117090:MAP4K4 protein, human
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