A Macrophage NBR1-MEKK3 Complex Triggers JNK-Mediated Adipose Tissue Inflammation in Obesity

Hernandez, Eloy D., Lee, Sang Jun, Kim, Ji Young, Duran, Angeles, Linares, Juan F., Yajima, Tomoko, Mueller, Timo D., Tschoep, Matthias H., Smith, Steven R., Diaz-Meco, Maria T., Moscat, Jorge

Supported by NIH Grants R01DK088107 (J.M.), R01CA172025 (J.M.), R01CA134530 (M. T. D.-M.), 5P30CA030199 (M. T. D.-M. and J.M.), and CCSPG Pilot Project Grant under award 5P30CA030199 (to M. T. D.-M. and S. S.) funded this work. The "healthy population'' clinical protocol was supported by U.S. Department of Agriculture Grant 2003-34323-14010 and the National Institutes of Health Clinical Nutrition Research Unit DK072476-01, and GlaxoSmithKline supported the parent "metabolic syndrome'' clinical study that was the source of the adipose tissue for this study. We thank Christine Blaumueller for editing this manuscript; Diantha LaVine for the artwork; Xiayu Huang (Bioinformatics core) for statistical analysis; and the personnel of the Cell Imaging, Viral Vectors, Functional Genomics, Animal Facility, and Histopathology Shared Resources at SBMRI and the UCSD Animal Care Program for technical assistance. We also thank Hui Xie, PhD, TRI-MD, Florida Hospital, for data and statistical support and Meghan Gabriel, SBMRI, for the human adipose tissue gene expression studies.

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.

A Macrophage NBR1-MEKK3 Complex Triggers JNK-Mediated Adipose Tissue Inflammation in Obesity Article