期刊
CLINICAL SCIENCE
卷 128, 期 8, 页码 493-506出版社
PORTLAND PRESS LTD
DOI: 10.1042/CS20140414
关键词
chronic inflammation; comparative gene identification-58 (CGI-58); forkhead box-containing protein O subfamily-1 (FOXO1); insulin resistance; interleukin 1 beta (IL-1 beta); obesity
资金
- National Natural Science Foundation of China [81302136, 81370063, 30973430, 81272364]
- China Postdoctoral Science Foundation [2013M542437]
- National Institute of Diabetes and Digestive and Kidney Diseases, U.S.A [R01DK085176]
Over-nutrition induces low-grade inflammation that dampens insulin sensitivity, but the underlying molecular mediators are not fully understood. Comparative gene identification-58 (CGI-58) is an intracellular lipolytic activator. In the present study, we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes, CGI-58 negatively and interleukin (IL)-1 beta positively correlate with obesity. Saturated non-esterified fatty acid (NEFA) suppresses CGI-58 expression in macrophages and this suppression activates FOXO1 (forkhead box-containing protein O subfamily-1) through inhibition of FOXO1 phosphorylation. Activated FOXO1 binds to an insulin-responsive element in IL-1 beta promoter region to potentiate IL-1 beta transcription. Gain-and loss-of-function studies demonstrate that NEFA-induced CGI-58 suppression activates FOXO1 to augment IL-1 beta transcription by dampening insulin signalling through induction of SOCS3 (suppressor of cytokine signalling 3) expression. CGI-58 deficiency-induced SOCS3 expression is NLRP3 (nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3) inflammasome-dependent. Our data thus identified a vicious cycle (IL-1 beta-SOCS3-FOXO1-IL-1 beta) that amplifies IL-1 beta secretion and is initiated by CGI-58 deficiency-induced activation of the NLRP3 inflammasome in macrophages. We further show that blocking this cycle with a FOXO1 inhibitor, an antioxidant that inhibits FOXO1 or IL-1 receptor antagonist alleviates chronic inflammation and insulin resistance in high-fat diet (HFD)-fed mice. Collectively, our data suggest that obesity-associated factors such as NEFA and lipopolysaccharide (LPS) probably adopt this vicious cycle to promote inflammation and insulin resistance.
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