title: Macrophage CGI-58 deficiency promotes IL-1β transcription by activating the SOCS3-FOXO1 pathway.
abstract: 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.
authors.affiliation: *Department of Oncology, Southwest hospital, The Third Military Medical University, Chongqing 400038, China.
authors.forename: Hongming
authors.initials: H
authors.lastname: Miao
authors.affiliation: *Department of Oncology, Southwest hospital, The Third Military Medical University, Chongqing 400038, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Ou
authors.affiliation: *Department of Oncology, Southwest hospital, The Third Military Medical University, Chongqing 400038, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: *Department of Oncology, Southwest hospital, The Third Military Medical University, Chongqing 400038, China.
authors.forename: Yujuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: ‡Department of Biology, Georgia State University, Atlanta, GA 30303, U.S.A.
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xue
authors.affiliation: ‡Department of Biology, Georgia State University, Atlanta, GA 30303, U.S.A.
authors.forename: Hang
authors.initials: H
authors.lastname: Shi
authors.affiliation: †Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing 400038, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Gan
authors.affiliation: §Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, U.S.A.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: *Department of Oncology, Southwest hospital, The Third Military Medical University, Chongqing 400038, China.
authors.forename: Houjie
authors.initials: H
authors.lastname: Liang
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D015992:Body Mass Index; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008954:Models, Biological; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D015430:Weight Gain
chemical_list: D005227:Fatty Acids; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D058847:Inflammasomes; D055504:Insulin Receptor Substrate Proteins; D053583:Interleukin-1beta; C526298:Irs2 protein, mouse; C106644:SOCS3 protein, human; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; C492986:Abhd5 protein, mouse