title: Rosiglitazone promotes fatty acyl CoA accumulation and excessive glycogen storage in livers of mice without adiponectin.
abstract: OBJECTIVE
  The beneficial effects of rosiglitazone on non-alcoholic fatty liver disease (NAFLD) have been reported. Rosiglitazone treatment stimulates the production of adiponectin, an insulin-sensitizing adipokine with hepatoprotective functions. The present study aims to investigate the hepatic actions of rosiglitazone in mice without adiponectin.
  
  
  METHODS
  NAFLD was induced in wild type and adiponectin knockout (AKO) mice by high-fat diet feeding. After rosiglitazone treatment, mice were subjected to evaluations on systemic insulin sensitivity, lipid profiles, hepatic steatosis, and inflammation, as well as the expression and activity of key molecules involved in energy metabolism and mitochondrial functions.
  
  
  RESULTS
  Rosiglitazone treatment prevented hepatic inflammation and reduced the expression of pro-inflammatory cytokines in livers of wild type mice. In contrast, in livers of AKO mice, the same treatment induced severe hepatomegaly and microvesicular hepatosteatosis, and caused abnormal accumulation of fatty acyl CoA, glycogen, and their intermediate metabolites. Compared to wild type littermates, the anti-inflammatory and the mitochondria-stimulatory activity of rosiglitazone were largely attenuated in AKO mice. Replenishment with either adiponectin or uncoupling protein 2 (UCP2) significantly reduced fatty acyl CoA accumulation and increased mitochondrial activities in livers of rosiglitazone-treated AKO mice. In addition, adiponectin, but not UCP2, promoted the activation of glycogen synthase kinase 3beta (GSK3beta), a key molecule involved in regulating glycogen homeostasis.
  
  
  CONCLUSIONS
  Rosiglitazone elicits its protective functions against NAFLD largely through the induction of adiponectin, which prevents mitochondria stresses by promoting GSK3beta activation and UCP2 upregulation, two pathways coordinating the glucose and lipid metabolism in liver.
authors.affiliation: Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
authors.forename: Mingyan
authors.initials: M
authors.lastname: Zhou
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Paul K H
authors.initials: PK
authors.lastname: Tam
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Che
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000378:metabolism*; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007004:Hypoglycemic Agents / Q000633:toxicity; D007473:Ion Channels / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000633:toxicity*; D000071246:Uncoupling Protein 2
chemical_list: D000214:Acyl Coenzyme A; D052242:Adiponectin; C499919:Adipoq protein, mouse; D007004:Hypoglycemic Agents; D007473:Ion Channels; D008112:Liver Glycogen; D024101:Mitochondrial Proteins; D045162:Thiazolidinediones; C000604390:Ucp2 protein, mouse; D000071246:Uncoupling Protein 2; D000077154:Rosiglitazone; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D055372:AMP-Activated Protein Kinases