A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity

Cell Metab. 2014 Sep 2;20(3):499-511. doi: 10.1016/j.cmet.2014.06.008. Epub 2014 Jul 17.

Abstract

The c-Jun NH(2)-terminal kinase (JNK) is a critical determinant of obesity-associated inflammation and glucose intolerance. The upstream mechanisms controlling this pathway are still unknown. Here we report that the levels of the PB1 domain-containing adaptor NBR1 correlated with the expression of proinflammatory molecules in adipose tissue from human patients with metabolic syndrome, suggesting that NBR1 plays a key role in adipose-tissue inflammation. We also show that NBR1 inactivation in the myeloid compartment impairs the function, M1 polarization, and chemotactic activity of macrophages; prevents inflammation of adipose tissue; and improves glucose tolerance in obese mice. Furthermore, we demonstrate that an interaction between the PB1 domains of NBR1 and the mitogen-activated kinase kinase 3 (MEKK3) enables the formation of a signaling complex required for the activation of JNK. Together, these discoveries identify an NBR1-MEKK3 complex as a key regulator of JNK signaling and adipose tissue inflammation in obesity.

Publication types

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

MeSH terms

  • Adipose Tissue / immunology*
  • Adipose Tissue / pathology
  • Amino Acid Sequence
  • Animals
  • Cell Line
  • Cells, Cultured
  • Female
  • Gene Deletion
  • Humans
  • Inflammation / complications*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Insulin Resistance
  • Intracellular Signaling Peptides and Proteins
  • JNK Mitogen-Activated Protein Kinases / immunology*
  • MAP Kinase Kinase Kinase 3 / chemistry
  • MAP Kinase Kinase Kinase 3 / immunology*
  • Macrophages / immunology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Molecular Sequence Data
  • Obesity / complications*
  • Obesity / genetics
  • Obesity / immunology
  • Obesity / pathology
  • Proteins / chemistry
  • Proteins / genetics
  • Proteins / immunology*
  • Sequence Alignment

Substances

  • Intracellular Signaling Peptides and Proteins
  • NBR1 protein, human
  • Nbr1 protein, mouse
  • Proteins
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 3