Macrophage CGI-58 deficiency activates ROS-inflammasome pathway to promote insulin resistance in mice.
Overnutrition activates a proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here, we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)γ signaling. Consequently, they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from oversecreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the cocultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages.
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA; Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing 400038, China.
Hongming
H
Miao
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA; Department of Oncology, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
Juanjuan
J
Ou
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
Yinyan
Y
Ma
Department of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
Feng
F
Guo
Department of Internal Medicine, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
Zhenggang
Z
Yang
Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Melvin
M
Wiggins
Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Chaohong
C
Liu
Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, MD 20742, USA.
Wenxia
W
Song
Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
Xianlin
X
Han
Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
Miao
M
Wang
Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Qiang
Q
Cao
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
Bik-Ho Florence
BH
Chung
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
Dan
D
Yang
Department of Oncology, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China.
Houjie
H
Liang
Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Bingzhong
B
Xue
Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
Hang
H
Shi
Department of Biochemistry and Molecular Biology, The Third Military Medical University, Chongqing 400038, China. Electronic address: ganlixia@yahoo.com.
Lixia
L
Gan
Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA. Electronic address: lyu123@umd.edu.
Liqing
L
Yu
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000096:biosynthesis / Q000172:deficiency*; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D005227:Fatty Acids / Q000494:pharmacology; D058847:Inflammasomes / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species / Q000378:metabolism*
D002352:Carrier Proteins; D005227:Fatty Acids; D058847:Inflammasomes; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; C492986:Abhd5 protein, mouse