Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity
Dibenzazepine-Loaded Nanoparticles Induce Local Browning of White Adipose Tissue to Counteract Obesity
复制标题
DOI：
10.1016/j.ymthe.2017.05.020
复制
发表时间：
2017-07-05
影响因子：
12.4
通讯作者：
Deng, Meng
中科院分区：
文献类型：
--
作者：
Jiang, Chunhui;Cano-Vega, Mario Alberto;Deng, Meng
通过全身给药抑制Notch信号传导会触发白色脂肪细胞转化为米色脂肪细胞（褐变）并减少肥胖。然而，将这一发现转化为临床实践面临着潜在的脱靶副作用以及缺乏对米色脂肪细胞生物发生的位置和时间范围的控制的挑战。在这里，我们展示了一种刺激褐变的替代方法，使用由 FDA 批准的聚丙交酯乙交酯共聚物组成的纳米颗粒 (NP)，该纳米颗粒能够持续局部释放 Notch 抑制剂（二苯并氮杂卓，DBZ）。这些负载 DBZ 的 NP 支持快速细胞内化并抑制脂肪细胞中的 Notch 信号传导。重要的是，将这些 NP 局部注射到饮食诱导的肥胖小鼠的腹股沟白色脂肪组织库中，会导致局部 NP 保留和脂肪细胞褐变，从而改善葡萄糖稳态并减弱治疗小鼠的体重增加。这些发现为开发临床治疗肥胖及其相关代谢综合征的潜在治疗策略提供了新途径。
Inhibition of Notch signaling via systemic drug administration triggers conversion of white adipocytes into beige adipocytes (browning) and reduces adiposity. However, translation of this discovery into clinical practice is challenged by potential off target side effects and lack of control over the location and temporal extent of beige adipocyte biogenesis. Here, we demonstrate an alternative approach to stimulate browning using nanoparticles (NPs) composed of FDA-approved poly(lactide-co-glycolide) that enable sustained local release of a Notch inhibitor (dibenzazepine, DBZ). These DBZ-loaded NPs support rapid cellular internalization and inhibit Notch signaling in adipocytes. Importantly, focal injection of these NPs into the inguinal white adipose tissue depots of diet-induced obese mice results in localized NP retention and browning of adipocytes, consequently improving the glucose homeostasis and attenuating body-weight gain of the treated mice. These findings offer new avenues to develop a potential therapeutic strategy for clinical treatment of obesity and its associated metabolic syndrome.