title: Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties.
abstract: OBJECTIVE
  The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is an important gene regulator in glucose and lipid metabolism. Unfortunately, PPARγ-activating drugs of the thiazolidinedione class provoke adverse side effects. As recently shown, amorfrutin A1 is a natural glucose-lowering compound that selectively modulates PPARγ. In this study we aimed to characterise, in vitro, a large spectrum of the amorfrutins and similar molecules, which we isolated from various plants. We further studied in vivo the glucose-lowering effects of the so far undescribed amorfrutin B, which featured the most striking PPARγ-binding and pharmacological properties of this family of plant metabolites.
  
  
  METHODS
  Amorfrutins were investigated in vitro by binding and cofactor recruitment assays and by transcriptional activation assays in primary human adipocytes and murine preosteoblasts, as well as in vivo using insulin-resistant high-fat-diet-fed C57BL/6 mice treated for 27 days with 100 mg kg(-1) day(-1) amorfrutin B.
  
  
  RESULTS
  Amorfrutin B showed low nanomolar binding affinity to PPARγ, and micromolar binding to the isotypes PPARα and PPARβ/δ. Amorfrutin B selectively modulated PPARγ activity at low nanomolar concentrations. In insulin-resistant mice, amorfrutin B considerably improved insulin sensitivity, glucose tolerance and blood lipid variables after several days of treatment. Amorfrutin B treatment did not induce weight gain and furthermore showed liver-protecting properties. Additionally, amorfrutins had no adverse effects on osteoblastogenesis and fluid retention.
  
  
  CONCLUSIONS
  The application of plant-derived amorfrutins or synthetic analogues thereof constitutes a promising approach to prevent or treat complex metabolic diseases such as insulin resistance or type 2 diabetes.
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Weidner
authors.forename: S J
authors.initials: SJ
authors.lastname: Wowro
authors.forename: A
authors.initials: A
authors.lastname: Freiwald
authors.forename: K
authors.initials: K
authors.lastname: Kawamoto
authors.forename: A
authors.initials: A
authors.lastname: Witzke
authors.forename: M
authors.initials: M
authors.lastname: Kliem
authors.forename: K
authors.initials: K
authors.lastname: Siems
authors.forename: L
authors.initials: L
authors.lastname: Müller-Kuhrt
authors.forename: F C
authors.initials: FC
authors.lastname: Schroeder
authors.forename: S
authors.initials: S
authors.lastname: Sauer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000819:agonists*; D012459:Salicylates / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012459:Salicylates; C582540:amorfrutin B