Macrophage CGI-58 deficiency promotes IL-1{beta} transcription by activating the SOCS3-FOXO1 pathway

Overnutrition 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. Here we show that in mouse visceral fat-derived macrophages or human peripheral blood monocytes CGI-58 negatively and IL-1β positively correlate with obesity. Saturated free fatty acid (FFA) suppresses CGI-58 expression in macrophages, and this suppression activates FOXO1 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 FFA-induced CGI-58 suppression activates FOXO1 to augment IL-1β transcription by dampening insulin signaling through induction of SOCS3 expression. CGI-58 deficiency-induced SOCS3 expression is NLRP3 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-fed mice. Collectively our data suggest that obesity-associated factors such as FFA and lipopolysaccharide likely a...

Source: Clinical Science - November 28, 2014 Category: Biomedical Science Authors: H Miao, J Ou, X Zhang, Y Chen, B Xue, H Shi, L Gan, L Yu, H Liang Source Type: research