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

  • Nat Commun. 2014 Aug 6:5:4602. doi: 10.1038/ncomms5602.
Huai-Chia Chuang  1 ,  Wayne H-H Sheu  2 ,  Yi-Ting Lin  1 ,  Ching-Yi Tsai  1 ,  Chia-Yu Yang  1 ,  Yu-Jhen Cheng  1 ,  Pau-Yi Huang  1 ,  Ju-Pi Li  1 ,  Li-Li Chiu  3 ,  Xiaohong Wang  4 ,  Min Xie  5 ,  Michael D Schneider  6 ,  Tse-Hua Tan  7
Affiliations
  • 1. Immunology Research Center, National Health Research Institutes, 35 Keyan Road, Zhunan 35053, Taiwan.
  • 2. 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.
  • 3. Division of Endocrinology and Metabolism, Taichung Veterans General Hospital, 160, Sec. 3, Chung-Kang Road, Taichung 40705, Taiwan.
  • 4. Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
  • 5. UT Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
  • 6. 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.
  • 7. 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.
PMID: 25098764 DOI: 10.1038/ncomms5602
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.