title: Lipid-induced Muscle Insulin Resistance Is Mediated by GGPPS via Modulation of the RhoA/Rho Kinase Signaling Pathway.
abstract: Elevated circulating free fatty acid levels are important contributors to insulin resistance in the muscle and liver, but the underlying mechanisms require further elucidation. Here, we show that geranylgeranyl diphosphate synthase 1 (GGPPS), which is a branch point enzyme in the mevalonic acid pathway, promotes lipid-induced muscle insulin resistance through activation of the RhoA/Rho kinase signaling pathway. We have found that metabolic perturbation would increase GGPPS expression in the skeletal muscles of db/db mice and high fat diet-fed mice. To address the metabolic effects of GGPPS activity in skeletal muscle, we generated mice with specific GGPPS deletions in their skeletal muscle tissue. Heterozygous knock-out of GGPPS in the skeletal muscle improved systemic insulin sensitivity and glucose homeostasis in mice fed both normal chow and high fat diets. These metabolic alterations were accompanied by activated PI3K/Akt signaling and enhanced glucose uptake in the skeletal muscle. Further investigation showed that the free fatty acid-stimulated GGPPS expression in the skeletal muscle was able to enhance the geranylgeranylation of RhoA, which further induced the inhibitory phosphorylation of IRS-1 (Ser-307) by increasing Rho kinase activity. These results implicate a crucial role of the GGPPS/RhoA/Rho kinase/IRS-1 pathway in skeletal muscle, in which it mediates lipid-induced systemic insulin resistance in obese mice. Therefore, skeletal muscle GGPPS may represent a potential pharmacological target for the prevention and treatment of obesity-related type 2 diabetes.
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tao
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Bing-Xian
authors.initials: BX
authors.lastname: Xie
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Zhao
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Xiu-Xing
authors.initials: XX
authors.lastname: Wang
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China xuebin@nju.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.affiliation: From the Ministry of Education Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the School of Medicine, Nanjing University, Nanjing 210061, China licj@nju.edu.cn.
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology; D051231:Farnesyltranstransferase / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D051379:Mice; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000201:enzymology; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C495428:Ggps1 protein, mouse; D009097:Multienzyme Complexes; D051231:Farnesyltranstransferase; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein
keywords: GGPPS; Ras homolog gene family, member A (RhoA); glucose metabolism; insulin resistance; protein isoprenylation; skeletal muscle