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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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3T3-L1 Cells
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Adipose Tissue / metabolism
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Animals
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CD3 Complex / metabolism
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CD4-Positive T-Lymphocytes / cytology
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Cell Differentiation
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Exons
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Fibroblasts / metabolism
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Glucose Tolerance Test
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HEK293 Cells
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Humans
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Inflammation
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Insulin Resistance*
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Interleukin-17 / metabolism
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Interleukin-2 Receptor alpha Subunit / metabolism
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Interleukin-6 / metabolism
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Jurkat Cells
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Lymphocytes / metabolism
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Lysosomes / metabolism
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Mice
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Mice, Knockout
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NF-kappaB-Inducing Kinase
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Receptors, Leptin / metabolism
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Signal Transduction
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TNF Receptor-Associated Factor 2 / metabolism*
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Th17 Cells / cytology*
Substances
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CD3 Complex
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Interleukin-17
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Interleukin-2 Receptor alpha Subunit
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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Receptors, Leptin
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TNF Receptor-Associated Factor 2
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MAP4K4 protein, human
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Protein Serine-Threonine Kinases