A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity.
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.
Mesh Terms:
Adipose Tissue, Amino Acid Sequence, Animals, Cell Line, Cells, Cultured, Female, Gene Deletion, Humans, Inflammation, Insulin Resistance, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 3, Macrophages, Male, Mice, Molecular Sequence Data, Obesity, Proteins, Sequence Alignment
Adipose Tissue, Amino Acid Sequence, Animals, Cell Line, Cells, Cultured, Female, Gene Deletion, Humans, Inflammation, Insulin Resistance, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 3, Macrophages, Male, Mice, Molecular Sequence Data, Obesity, Proteins, Sequence Alignment
Cell Metab.
Date: Sep. 02, 2014
PubMed ID: 25043814
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