A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity

摘要

"脂肪细胞因子"(Adiponectin)是来自脂肪的一种荷尔蒙，似乎在防止胰岛素抗性/糖尿病和动脉粥样硬化中起关键作用。这项研究发现了一种口服活性化合物，是通过对东京大学"药物发现开放创新中心"的化学库中的小分子进行筛选获得的，它与介导"脂肪细胞因子"的抗糖尿病作用的AdipoR1和AdipoR2受体结合，并激活这两个受体。被命名为AdipoRon的这种化合物能减轻吃高脂肪食物的小鼠和遗传性肥胖小鼠的胰岛素抗性和葡萄糖耐受不良。AdipoRon还能延长吃高脂肪食物的db/db小鼠被縮短的寿命。如果这项工作可以被外推到人类，那么像AdipoRon这样的口服活性激动剂就可能为治疗如2-型糖尿病等与肥胖相关的疾病提供一个有希望的新方法。%Adiponectin secreted from adipocytes binds to adiponectin receptors AdipoR1 and AdipoR2, and exerts antidiabetic effects via activation of AMPK and PPAR-α pathways, respectively. Levels of adiponectin in plasma are reduced in obesity, which causes insulin resistance and type 2 diabetes. Thus, orally active small molecules that bind to and activate AdipoR1 and AdipoR2 could ameliorate obesity-related diseases such as type 2 diabetes. Here we report the identification of orally active synthetic small-molecule AdipoR agonists. One of these compounds, AdipoR agonist (AdipoRon), bound to both AdipoR1 and AdipoR2 in vitro. AdipoRon showed very similar effects to adiponectin in muscle and liver, such as activation of AMPK and PPAR-α pathways, and ameliorated insulin resistance and glucose intolerance in mice fed a high-fat diet, which was completely obliterated in AdipoR1 and AdipoR2 double-knockout mice. Moreover, AdipoRon ameliorated diabetes of genetically obese rodent model db/db mice, and prolonged the shortened lifespan of db/db mice on a high-fat diet. Thus, orally active AdipoR agonists such as AdipoRon are a promising therapeutic approach for the treatment of obesity-related diseases such as type 2 diabetes.