HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance

Huai-Chia Chuang, Wayne H. -H. Sheu, Yi-Ting Lin, Ching-Yi Tsai, Chia-Yu Yang, Yu-Jhen Cheng, Pau-Yi Huang, Ju-Pi Li, Li-Li Chiu, Xiaohong Wang, Min Xie, Michael D. Schneider () and Tse-Hua Tan ()
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Huai-Chia Chuang: Immunology Research Center, National Health Research Institutes
Wayne H. -H. Sheu: Taichung Veterans General Hospital
Yi-Ting Lin: Immunology Research Center, National Health Research Institutes
Ching-Yi Tsai: Immunology Research Center, National Health Research Institutes
Chia-Yu Yang: Immunology Research Center, National Health Research Institutes
Yu-Jhen Cheng: Immunology Research Center, National Health Research Institutes
Pau-Yi Huang: Immunology Research Center, National Health Research Institutes
Ju-Pi Li: Immunology Research Center, National Health Research Institutes
Li-Li Chiu: Taichung Veterans General Hospital
Xiaohong Wang: Baylor College of Medicine
Min Xie: UT Southwestern Medical Center at Dallas
Michael D. Schneider: Faculty of Medicine, British Heart Foundation Centre of Research Excellence, National Heart and Lung Institute, Imperial College London
Tse-Hua Tan: Immunology Research Center, National Health Research Institutes

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5602

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