Drug development research for novel adiponectin receptor-targeted antidiabetic drugs contributing to healthy longevity
Drug development research for novel adiponectin receptor-targeted antidiabetic drugs contributing to healthy longevity
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有助于健康长寿的新型脂联素受体靶向抗糖尿病药物的药物开发研究
DOI：
10.1007/s13340-019-00409-6
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发表时间：
2019
影响因子：
2.2
通讯作者：
Kadowaki Takashi
中科院分区：
文献类型：
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作者：
Okada-Iwabu Miki;Iwabu Masato;Yamauchi Toshimasa;Kadowaki Takashi
脂联素水平的降低与高脂饮食和缺乏运动有关，是胰岛素抵抗、2型糖尿病、代谢综合征和心血管疾病的发病原因。我们的研究工作已经导致脂联素受体AdipoR 1和AdipoR 2的鉴定，前者显示激活肝脏中的AMP激酶，后者显示激活过氧化物酶体增殖物激活受体-α信号传导，从而增加脂肪酸氧化。同样，脂联素上调骨骼肌中的线粒体功能，从而改善葡萄糖/脂质代谢和胰岛素抵抗。这些发现表明，脂联素/AdipoR信号传导的激活可以代表与普遍肥胖相关的生活方式相关疾病的可行治疗方法，从而有助于人类的健康长寿。事实上，他们已经成功发现了AdipoRon，一种小分子AdipoR激活化合物。到目前为止，AdipoRon不仅可以改善小鼠的胰岛素抵抗，还可以延长因高脂肪饮食而缩短的寿命。此外，我们基于结构的药物发现研究已经导致AdipoR被鉴定为一种全新的结构，其具有在其七跨膜结构域内结合的锌铁，以及与G蛋白偶联受体相反的方向。预计对AdipoR信号传导的深入了解将促进候选小分子AdipoR激活化合物的结构优化，以及用于生活方式相关疾病的分子靶向和卡路里限制/运动模拟剂的开发。
It is well recognized that the decrease of adiponectin associated with high-fat diet and lack of exercise accounts for the onset of insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Our research efforts have led to the identification of adiponectin receptors, AdipoR1 and AdipoR2, with the former shown to activate AMP kinase in the liver and the latter shown to activate peroxisome proliferator-activated receptor-α signaling thereby increasing fatty acid oxidation. Again, adiponectin upregulates mitochondrial function in the skeletal muscle thereby improving glucose/lipid metabolism and insulin resistance. These findings suggested that activation of adiponectin/AdipoR signaling could represent a viable therapeutic approach to lifestyle-linked diseases associated with prevalent obesity thus contributing to healthy longevity in humans. Indeed, they have led to the successful discovery of AdipoRon, a small-molecule AdipoR-activating compound. Thus far, AdipoRon has been found not only to improve insulin resistance in mice but to prolong their lifespan shortened by high-fat diet. Additionally, our structure-based drug discovery research has led to AdipoR being identified as an entirely novel structure having a zinc iron bound within its seven-transmembrane domain as well as an opposite orientation to that of G protein-coupled receptors. It is expected that increasing insight into AdipoR signaling will facilitate the structure-based optimization of candidate small-molecule AdipoR-activating compounds for human use as well as the development of molecularly targeted and calorie-limiting/exercise-mimicking agents for lifestyle-linked diseases.