期刊
CELL METABOLISM
卷 20, 期 3, 页码 499-511出版社
CELL PRESS
DOI: 10.1016/j.cmet.2014.06.008
关键词
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资金
- NIH [R01DK088107, R01CA172025, R01CA134530, 5P30CA030199]
- CCSPG Pilot Project [5P30CA030199]
- U.S. Department of Agriculture [2003-34323-14010]
- National Institutes of Health Clinical Nutrition Research Unit [DK072476-01]
- GlaxoSmithKline
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.
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