title: Beneficial direct adipotropic actions of pitavastatin in vitro and their manifestations in obese mice.
abstract: OBJECTIVE
  Prevention of cardiovascular complications in obese patients frequently includes statin administration for coexisting dyslipidemia. Herein, we investigated the impacts of pitavastatin at clinically relevant doses on adipose dysfunction and insulin resistance.
  
  
  METHODS
  We treated 3T3-L1 preadipocytes with 10-100 ng/ml pitavastatin from initiation of differentiation (Day 0) to Day 8 (differentiation/maturation phase) or from Day 8 to Day 16 (post-maturation phase). Subsequently, we administered pitavastatin (6.2mg/day/kg) to 7-week-old female KKAy mice for 6 weeks; untreated KKAy mice served as obese controls.
  
  
  RESULTS
  Pitavastatin impaired neither lipogenesis nor adiponectin expression during the differentiation/maturation phase. During the post-maturation phase, pitavastatin prevented excessive triglyceride accumulation, which was associated with attenuated glucose transporter-4 expression, and dose-dependently upregulated hormone-sensitive lipase expression. Decrements in the adiponectin/plasminogen activator-1 ratio were also dose-dependently inhibited. In KKAy mice, Coulter counter analyses revealed that pitavastatin treatment significantly decreased (by 16.8%) the frequency of hypertrophic adipocytes (>150 microm in diameter) in parametrial adipose pads, of which total weight remained unaltered. Correspondingly, plasma adiponectin was significantly higher in pitavastatin-treated KKAy mice than in the untreated KKAy mice (12.5+/-3.8 microg/ml vs. 8.3+/-1.5 microg/ml, p<0.05). Moreover, the area under the time-glucose curve after intraperitoneal insulin was decreased by 16% in pitavastatin-treated KKAy mice (p<0.05 vs. untreated controls).
  
  
  CONCLUSIONS
  Pitavastatin did not impair differentiation/maturation of preadipocytes and prevented their deterioration with hypertrophy after maturation at clinical concentrations in vitro. These effects likely contributed to improved insulin sensitivity, in an obese model, via prevention of adipocyte hypertrophy and adipocytokine dysregulation.
authors.affiliation: Department of Cardiorenal Cerebrovascular Medicine, Kagawa University Faculty of Medicine, 1750-1 Ikenobe, Miki-cho, Kagawa 761-0793, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
authors.forename: Mizuki
authors.initials: M
authors.lastname: Mizukawa
authors.forename: Arif Ul
authors.initials: AU
authors.lastname: Hasan
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noma
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D048429:Cell Size / Q000187:drug effects; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006984:Hypertrophy; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050155:Lipogenesis / Q000187:drug effects; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D011804:Quinolines; C495693:Slc2a4 protein, mouse; D014280:Triglycerides; D008071:Lipoprotein Lipase; C108475:pitavastatin