Title | A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. |
Publication Type | Journal Article |
Year of Publication | 2014 |
Authors | Hernandez ED, Lee SJun, Kim JYoung, Duran A, Linares JF, Yajima T, Müller TD, Tschöp MH, Smith SR, Diaz-Meco MT, Moscat J |
Journal | Cell Metab |
Volume | 20 |
Issue | 3 |
Pagination | 499-511 |
Date Published | 2014 Sep 02 |
ISSN | 1932-7420 |
Keywords | Adipose Tissue, Amino Acid Sequence, Animals, Cell Line, Cells, Cultured, Female, Gene Deletion, Humans, Inflammation, Insulin Resistance, Intracellular Signaling Peptides and Proteins, JNK Mitogen-Activated Protein Kinases, Macrophages, Male, MAP Kinase Kinase Kinase 3, Mice, Molecular Sequence Data, Obesity, Proteins, Sequence Alignment |
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. |
DOI | 10.1016/j.cmet.2014.06.008 |
Alternate Journal | Cell Metab |
PubMed ID | 25043814 |
PubMed Central ID | PMC4156534 |
Grant List | R01DK088107 / DK / NIDDK NIH HHS / United States R01CA134530 / CA / NCI NIH HHS / United States 5P30CA030199 / CA / NCI NIH HHS / United States R01CA172025 / CA / NCI NIH HHS / United States |
Related Lab:
Related Faculty:
Jorge Moscat, Ph.D. Juan Francisco Linares Rodriguez, Ph.D. Maria Diaz-Meco Conde, Ph.D.