HGK/MAP4K4 deficiency induces TRAF2 stabilization and Th17 differentiation leading to insulin resistance
Author(s)
Type
Journal Article
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.
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 Issued
2014-08-06
Date Acceptance
2014-07-07
Citation
Nature Communications, 2014, 5 (7)
ISSN
2041-1723
Publisher
Nature Publishing Group
Journal / Book Title
Nature Communications
Volume
5
Issue
7
Copyright Statement
This work is licensed under a Creative Commons Attribution Non Commercial-No Derivs
4.0 International License. The images or
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license, unless indicated otherwise in the credit line; if the material is not included under
the Creative Commons license, users will need to obtain permission from the license
holder to reproduce the material. To view a copy of this license, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/
4.0 International License. The images or
other third party material in this article are included in the article’s Creative Commons
license, unless indicated otherwise in the credit line; if the material is not included under
the Creative Commons license, users will need to obtain permission from the license
holder to reproduce the material. To view a copy of this license, visit http://
creativecommons.org/licenses/by-nc-nd/4.0/
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
NECROSIS-FACTOR-ALPHA
N-TERMINAL KINASE
CD4(+) T-CELLS
SKELETAL-MUSCLE
KAPPA-B
LIVER INFLAMMATION
SIGNALING PATHWAY
LIPID-METABOLISM
LEPTIN RECEPTOR
PROTEIN-KINASE
Publication Status
Published
Article Number
ARTN 4602