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

Nat Commun. 2014 Aug 6;5:4602. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • 3T3-L1 Cells
  • Adipose Tissue / metabolism
  • Animals
  • CD3 Complex / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • Cell Differentiation
  • Exons
  • Fibroblasts / metabolism
  • Glucose Tolerance Test
  • HEK293 Cells
  • Humans
  • Inflammation
  • Insulin Resistance*
  • Interleukin-17 / metabolism
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukin-6 / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Jurkat Cells
  • Lymphocytes / metabolism
  • Lysosomes / metabolism
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptors, Leptin / metabolism
  • Signal Transduction
  • TNF Receptor-Associated Factor 2 / metabolism*
  • Th17 Cells / cytology*

Substances

  • CD3 Complex
  • Interleukin-17
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-6
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Leptin
  • TNF Receptor-Associated Factor 2
  • MAP4K4 protein, human
  • Protein-Serine-Threonine Kinases
  • NF-kappa B kinase