Amorfrutin B is an efficient natural peroxisome proliferator-activated receptor gamma (PPARγ) agonist with potent glucose-lowering properties.

Abstract

AIMS/HYPOTHESIS:

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/INTERPRETATION:

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: C Weidner, S J Wowro, A Freiwald, K Kawamoto, A Witzke, M Kliem, K Siems, L Müller-Kuhrt, F C Schroeder, S Sauer
• Journal: Diabetologia (Diabetologia) Vol. 56 Issue 8 Pg. 1802-12 (Aug 2013) ISSN: 1432-0428 [Electronic] Germany
• PMID: 23680913 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoglycemic Agents
• PPAR gamma
• Salicylates
• amorfrutin B

Topics

• Animals
• Cells, Cultured
• Diabetes Mellitus, Type 2 (drug therapy)
• Humans
• Hypoglycemic Agents (therapeutic use)
• Insulin Resistance (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• PPAR gamma (agonists)
• Salicylates (therapeutic use)