Amorfrutins are selective PPARγ agonists with potent antidiabetic properties. Amorfrutins are selective PPARγ agonists with potent antidiabetic properties

Faced by an alarming incidence of metabolic diseases including obesity and type 2 diabetes worldwide, there is an urgent need for effective strategies for preventing and treating these common diseases. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a crucial role in metabolism. We isolated the amorfrutins from edible parts of the plants Glychyrrhiza foetida and Amorpha fruticosa, and identified these natural products as a new chemical class to treat insulin resistance and diabetes by selectively activating PPARγ. In contrast to existing synthetic PPARγ drugs, the amorfrutins display unique properties by separating insulin sensitization from unwanted side effects. In obese mouse models, amorfrutin treatment significantly improved important metabolic and inflammatory parameters. In summary, PPARγ activation by selective amorfrutins derived from edible biomaterial is a promising approach to combat metabolic diseases and other diseases in which PPARγ is involved in. Overall design: GSM701612-GSM701623: Male DIO C57BL/6 mice (age 18 wks), 3 groups (n=4 each after pooling of 8 samples per group). Mice were fed over 3 wks with high fat diet (HFD) without compound (vehicle), HFD with 4 mg/kg/d rosiglitazone or with 100 mg/kg/d amorfrutin 1. Liver RNA extracted. --> 4 biological replicates, vehicle vs. rosiglitazone or amorfrutin 1 GSM702299-GSM702344: Biological replicates (n = 3-4 each) of human primary adipocytes were treated with the following compounds for 24 hours. 10µM rosiglitazone, 10µM pioglitazone, 30µM telmisartan, 10µM nTZDpa, 30µM amorfrutin 1, 30µM amorfrutin 2, 30µM amorfrutin 3 or 30µM amorfrutin 4 vs. 0.1% DMSO (vehicle)

全球范围内肥胖、2型糖尿病等代谢疾病的发病率令人警觉，亟需开发有效的防治策略以应对这类常见疾病。过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma，PPARγ）在代谢调控中发挥关键作用。本研究从Glychyrrhiza foetida与Amorpha fruticosa的可食用部位中分离得到阿莫罗弗汀（amorfrutins），并证实这类天然产物为全新化学类别，可通过选择性激活PPARγ治疗胰岛素抵抗与糖尿病。与现有合成PPARγ类药物不同，阿莫罗弗汀具备独特特性，可将胰岛素增敏作用与不良副作用相分离。在肥胖小鼠模型中，阿莫罗弗汀给药可显著改善关键代谢与炎症参数。综上，源自可食用生物材料的选择性PPARγ激活剂阿莫罗弗汀，是对抗代谢疾病及其他PPARγ参与疾病的极具前景的策略。

整体实验设计：
1. GSM701612-GSM701623：选取18周龄雄性饮食诱导肥胖（DIO）C57BL/6小鼠，分为3组，每组经8只样本合并后获得4个生物学重复。小鼠经高脂饮食（HFD）分别联合空白溶剂（vehicle）、4 mg/kg/d罗格列酮或100 mg/kg/d amorfrutin 1干预3周。提取肝脏RNA，设置4个生物学重复，分别对比溶剂组与罗格列酮组或amorfrutin 1组。
2. GSM702299-GSM702344：人类原代脂肪细胞的生物学重复（每组3-4个）分别用以下化合物处理24小时：10μM罗格列酮、10μM吡格列酮、30μM替米沙坦、10μM nTZDpa、30μM amorfrutin 1、30μM amorfrutin 2、30μM amorfrutin 3、30μM amorfrutin 4，同时设置0.1%二甲基亚砜（DMSO）作为溶剂对照。