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)-1β 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-1β promoter region to potentiate IL-1β transcription. Gain- and loss-of-function studies demonstrate that NEFA-induced CGI-58 suppression activates FOXO1 to augment IL-1β 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-1β–SOCS3–FOXO1–IL-1β) that amplifies IL-1β 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.
Macrophage CGI-58 deficiency promotes IL-1β transcription by activating the SOCS3–FOXO1 pathway
- Views Icon Views
- Share Icon Share
Hongming Miao, Juanjuan Ou, Xuan Zhang, Yujuan Chen, Bingzhong Xue, Hang Shi, Lixia Gan, Liqing Yu, Houjie Liang; Macrophage CGI-58 deficiency promotes IL-1β transcription by activating the SOCS3–FOXO1 pathway. Clin Sci (Lond) 1 April 2015; 128 (8): 493–506. doi: https://doi.org/10.1042/CS20140414
Download citation file: