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Nat Commun. 2014 Aug 6;5:4602. doi: 10.1038/ncomms5602.

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

Author information

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.

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.

PMID:
25098764
PMCID:
PMC4143962
DOI:
10.1038/ncomms5602
[Indexed for MEDLINE]
Free PMC Article

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