Muscle-specific deletion of comparative gene identification-58 (CGI-58) causes muscle steatosis but improves insulin sensitivity in male mice.
Intramyocellular accumulation of lipids is often associated with insulin resistance. Deficiency of comparative gene identification-58 (CGI-58) causes cytosolic deposition of triglyceride (TG)-rich lipid droplets in most cell types, including muscle due to defective TG hydrolysis. It was unclear, however, whether CGI-58 deficiency-induced lipid accumulation in muscle influences insulin sensitivity. Here we show that muscle-specific CGI-58 knockout mice relative to their controls have increased glucose tolerance and insulin sensitivity on a Western-type high-fat diet, despite TG accumulation in both heart and oxidative skeletal muscle and cholesterol deposition in heart. Although the intracardiomyocellular lipid deposition results in cardiac ventricular fibrosis and systolic dysfunction, muscle-specific CGI-58 knockout mice show increased glucose uptake in heart and soleus muscle, improved insulin signaling in insulin-sensitive tissues, and reduced plasma concentrations of glucose, insulin, and cholesterol. Hepatic contents of TG and cholesterol are also decreased in these animals. Cardiac steatosis is attributable, at least in part, to decreases in cardiac TG hydrolase activity and peroxisome proliferator-activated receptor-α/peroxisome proliferator-activated receptor-γ coactivator-1-dependent mitochondrial fatty acid oxidation. In conclusion, muscle CGI-58 deficiency causes cardiac dysfunction and fat deposition in oxidative muscles but induces a series of favorable metabolic changes in mice fed a high-fat diet.
Departments of Biochemistry (P.X., Y.M., F.G., L.Y.) and Anesthesiology (L.G.), Wake Forest School of Medicine, Winston-Salem, North Carolina 27157; Department of Animal and Avian Sciences (A.K.G.G., Y.M., L.Y.), University of Maryland, College Park, Maryland 20742; Diabetes and Obesity Research Center (X.H., M.W.), Sanford-Burnham Medical Research Institute, Orlando, Florida 32827; Department of Biology (B.X., H.S.), Georgia State University, Atlanta, Georgia 30303; and The Key Laboratory of Remodeling-Related Cardiovascular Diseases (H.L.), Capital Medical University, Ministry of Education, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated the Capital Medical University, Beijing 100029, People's Republic of China.
Ping
P
Xie
Anil K G
AK
Kadegowda
Yinyan
Y
Ma
Feng
F
Guo
Xianlin
X
Han
Miao
M
Wang
Leanne
L
Groban
Bingzhong
B
Xue
Hang
H
Shi
Huihua
H
Li
Liqing
L
Yu
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics*; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D007333:Insulin Resistance; D008049:Lipase / Q000378:metabolism; D066292:Lipid Droplets / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology
D005227:Fatty Acids; D047493:PPAR alpha; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C492986:Abhd5 protein, mouse; D008049:Lipase; D005947:Glucose