Jiang Chunhui, Cano-Vega Mario Alberto, Yue Feng, Kuang Liangju, Narayanan Naagarajan, Uzunalli Gozde, Merkel Madeline P, Kuang Shihuan, Deng Meng
Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA; Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA.
Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
Mol Ther. 2017 Jul 5;25(7):1718-1729. doi: 10.1016/j.ymthe.2017.05.020. Epub 2017 Jun 16.
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.
通过全身给药抑制Notch信号传导可促使白色脂肪细胞转变为米色脂肪细胞（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无法控制米色脂肪细胞生成的位置和时间范围等挑战。在此，我们展示了一种使用由美国食品药品监督管理局（FDA）批准的聚（丙交酯-共-乙交酯）组成的纳米颗粒（NP）来刺激褐变的替代方法，该纳米颗粒能够使Notch抑制剂（二苯并氮杂卓，DBZ）持续局部释放。这些负载DBZ的NP支持细胞快速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肥胖小鼠的腹股沟白色脂肪组织库中会导致NP局部保留和脂肪细胞褐变，从而改善治疗小鼠的葡萄糖稳态并减轻体重增加。这些发现为开发肥胖及其相关代谢综合征临床治疗的潜在治疗策略提供了新途径。
