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.

中文翻译：

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Amorfrutin B 是一种有效的天然过氧化物酶体增殖物激活受体 γ (PPARγ) 激动剂，具有有效的降糖特性。

目的/假设 核受体过氧化物酶体增殖物激活受体 γ (PPARγ) 是葡萄糖和脂质代谢中的重要基因调节剂。不幸的是，噻唑烷二酮类 PPARγ 激活药物会引起不良副作用。最近表明，amorfrutin A1 是一种天然降糖化合物，可选择性调节 PPARγ。在这项研究中，我们的目标是在体外表征我们从各种植物中分离出的大范围苦杏仁苷和类似分子。我们进一步在体内研究了迄今为止尚未描述的 amorfrutin B 的降糖作用，它具有该植物代谢物家族最显着的 PPARγ 结合和药理特性。方法 通过结合和辅助因子募集试验以及原代人脂肪细胞和鼠前成骨细胞中的转录激活试验，以及使用胰岛素抵抗高脂肪饮食喂养的 C57BL/6 小鼠在体内进行了 27 天的治疗，对 Amorfrutins 进行了体外研究。 100 mg kg(-1) day(-1) amorfrutin B。 结果 Amorfrutin B 对 PPARγ 显示出低纳摩尔结合亲和力，与同种型 PPARα 和 PPARβ/δ 显示出微摩尔结合。Amorfrutin B 在低纳摩尔浓度下选择性调节 PPARγ 活性。在胰岛素抵抗小鼠中，经过几天的治疗，amorfrutin B 显着改善了胰岛素敏感性、葡萄糖耐量和血脂变量。Amorfrutin B 治疗不会导致体重增加，而且还显示出保护肝脏的特性。此外，amorfrutins 对成骨细胞生成和体液潴留没有不利影响。结论/解释 植物来源的苦杏仁苷或其合成类似物的应用构成了预防或治疗复杂代谢疾病（例如胰岛素抵抗或 2 型糖尿病）的有前途的方法。