title: A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity.
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.
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Eloy D
authors.initials: ED
authors.lastname: Hernandez
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Sang Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Linares
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yajima
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München & Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 85764 Munich, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München & Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 85764 Munich, Germany.
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.affiliation: Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Sanford-Burnham Medical Research Institute, FL 32789, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA. Electronic address: jmoscat@sanfordburnham.org.
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
mesh_terms: D000273:Adipose Tissue / Q000276:immunology* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D048031:JNK Mitogen-Activated Protein Kinases / Q000276:immunology*; D048748:MAP Kinase Kinase Kinase 3 / Q000737:chemistry / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D016415:Sequence Alignment
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C549756:NBR1 protein, human; C486326:Nbr1 protein, mouse; D011506:Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048748:MAP Kinase Kinase Kinase 3