title: A novel plasminogen activator inhibitor-1 inhibitor, TM5441, protects against high-fat diet-induced obesity and adipocyte injury in mice.
abstract: Obesity is one of the most prevalent chronic diseases worldwide, and dysregulated adipocyte function plays an important role in obesity-associated metabolic disorder. The level of plasma plasminogen activator inhibitor-1 (PAI-1) is increased in obese subjects, and PAI-1 null mice show improved insulin sensitivity when subjected to high-fat and high-sucrose diet-induced metabolic stress, suggesting that a best-in-class PAI-1 inhibitor may become a novel therapeutic agent for obesity-associated metabolic syndrome. TM5441 is a novel orally active PAI-1 inhibitor that does not cause bleeding episodes. Hence, in the present study we examined the preventive effect of TM5441 on high-fat diet (HFD)-induced adipocyte dysfunction.
  
  
  
  Ten-week-old C57BL/6J mice were fed a normal diet (18% of total calories from fat) or HFD (60% of total calories from fat) for 10 weeks, and TM5441 (20 mg·kg(-1) oral gavage) was administered daily with the initiation of HFD.
  
  
  
  TM5441 prevented HFD-induced body weight gain and systemic insulin resistance. TM5441 normalized HFD-induced dysregulated JNK and Akt phosphorylation, suggesting that it prevents the insulin resistance of adipocytes. TM5441 also attenuated the macrophage infiltration and increased expression of pro-inflammatory cytokines, such as inducible nitric oxide synthase, induced by the HFD. In addition, TM5441 prevented the HFD-induced down-regulation of genes involved in mitochondrial biogenesis and function, suggesting that it may prevent adipocyte inflammation and dysregulation by maintaining mitochondrial fitness.
  
  
  
  Our data suggest that TM5441 may become a novel therapeutic agent for obesity and obesity-related metabolic disorders.
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Lingjuan
authors.initials: L
authors.lastname: Piao
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Inji
authors.initials: I
authors.lastname: Jung
authors.affiliation: Colleges of Pharmacy, Chonnam National University, Gwang-Ju, Korea.
authors.forename: Joo Young
authors.initials: JY
authors.lastname: Huh
authors.affiliation: United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
authors.forename: Hunjoo
authors.initials: H
authors.lastname: Ha
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester; D009765:Obesity / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D058258:Serpin E2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D062366:para-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010879:Piperazines; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C000623364:TM5441; D062366:para-Aminobenzoates; D019331:NG-Nitroarginine Methyl Ester