title: Corosolic acid inhibits adipose tissue inflammation and ameliorates insulin resistance via AMPK activation in high-fat fed mice.
abstract: BACKGROUND
  Adipose tissue inflammation is tightly associated with the development of insulin resistance. Corosolic acid (CRA), a natural triterpenoid, is well known as "phyto-insulin" due to its insulin-like activities. However, its underlying mechanism remains unknown.
  
  
  OBJECTIVE
  In this study, we investigated the mechanisms of CRA on improving insulin resistance both in vivo and in vitro.
  
  
  METHODS
  C57BL/6 mice were fed with normal diet, high-fat diet (HFD) or HFD with CRA, respectively. General biochemical parameters in blood and glucose intolerance in mice were assayed. Meanwhile, proinflammatory cytokines and macrophage infiltrations in adipose tissues were analyzed by real-time PCR and immunohistochemical staining. The effects of CRA on insulin signaling transduction and AMPK activity in adipose tissues were investigated by western blot. Furthermore, the effects of CRA on AMPK were confirmed on 3T3-L1 cells by using both AMPK inhibitor and AMPKα1/2-specific siRNA RESULTS: CRA attenuated hyperlipidemia, improved insulin sensitivity and glucose intolerance in mice. Meanwhile, it alleviated inflammation in adipose tissues, demonstrated by the suppression of IKKβ phosphorylation and down-regulation of gene expressions of proinflammatory cytokines. Histological analysis revealed that CRA attenuated macrophage infiltrations into adipose tissue. It also improved insulin signaling transduction by modification of Ser/Thr phosphorylation of IRS-1 and downstream Akt, thereby improved insulin sensitivity in HFD-fed mice. Furthermore, CRA regulated AMPK activation in a LKB1-dependent manner. AMPKα knockdown in adipocytes abolished the inhibitory effects of CRA on IKKβ and IRS-1 serine phosphorylation, indicating that CRA inhibited inflammation and ameliorated insulin resistance via AMPK activation.
  
  
  CONCLUSIONS
  CRA inhibited inflammation with improvement in adipose tissue dysfunction and ameliorated insulin resistance in an AMPK-dependent manner.
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Leng
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.affiliation: Shanghai Hua Yu Chinese Herbs Co., Ltd, People's Republic of China.
authors.forename: Jing-fu
authors.initials: JF
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
authors.forename: Bao-Lin
authors.initials: BL
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural Medicines, Department of Chinese Medicines Analysis, China Pharmaceutical University, Nanjing 210009, People's Republic of China. Electronic address: xiaodongwen123@126.com.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wen
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects* / Q000503:physiopathology; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D015536:Down-Regulation; D018149:Glucose Intolerance / Q000503:physiopathology; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008264:Macrophages / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D007328:Insulin; D014315:Triterpenes; C113861:corosolic acid; D051550:I-kappa B Kinase; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Adipose tissue; Corosolic acid; Inflammation; Insulin resistance