Anti-obesity effect of NO-releasing Nanomatrix

摘要 衰老与肥胖相关的代谢紊乱有关，主要是由于代谢率降低。肥胖 在成人中是一种世界性的流行病，并导致严重的健康问题。生活方式干预，包括锻炼 而节食，则是推荐的最佳治疗方法。然而，效果往往不尽如人意，效果是 只是暂时的。运动和一氧化氮(NO)都会增加代谢率，这有助于转换 通过增加线粒体数量和能量将白色脂肪细胞转变为米色/棕色脂肪细胞(脂肪细胞的褐变) 制作。这一有利的举措使身体代谢更多的脂肪，减少脂肪量。然而，还有 目前还没有成功的治疗方法来改善与年龄相关的心脏代谢紊乱。自推广以来 “褐变”提高代谢率和改善心脏代谢功能，增强“褐变”在一个非 侵入性方式可能是预防年龄相关性心脏代谢性疾病的有效方法。我们的研究 该团队开发了生物兼容的NO释放纳米基质凝胶，这种凝胶可以在体内释放持续水平的NO。 因此，将释放NO的纳米基质凝胶植入白色脂肪组织可诱导脂肪细胞发生褐变。 我们观察到，与NO释放纳米基质凝胶孵育的细胞在体外诱导出棕色样脂肪细胞。从… 这些结果，我们假设SubQ给药NO释放的纳米基质凝胶是一种新的 通过促进脂肪细胞褐化来治疗年龄相关性代谢功能障碍的治疗策略。 为了检验这一假设；在目标1中，我们将确定皮下(SubQ)给药的效果- 纳米基质凝胶对老年小鼠肥胖和胰岛素抵抗的影响；在目标2中，我们将阐明 释放NO的纳米基质凝胶增强AT褐变的机制。完成这些目标将 为治疗年龄相关性肥胖和心脏代谢性疾病提供了一种新的策略。

ABSTRACT Aging is associated with obese-associated metabolic disorders mainly due to the reduced metabolic rate. Obesity in adults is a world-wide epidemic, and causes serious health problems. Lifestyle intervention, including exercise and diet, is recommended for the best treatment. However, the results are often unsatisfactory, and the effect is only temporary. Both exercise and nitric oxide (NO) increase metabolic rate, which contributes to converting white adipocyte to beige/brite adipocyte (browning of adipocyte) by increasing mitochondrial number and energy production. This favorable move makes the body metabolize more fat and reduce fat mass. However, there is no successful treatment available to improve age-associated cardiometabolic disorders. Since promotion of “browning” increases metabolic rate and improve cardiometabolic functions, enhancing “browning” in a non- invasive manner may be an efficient way of preventing age-associated cardiometabolic diseases. Our research team developed biocompatible NO-releasing nanomatrix gel, which can release sustained levels of NO in vivo. Therefore, implanting NO-releasing nanomatrx gel into white adipose tissue may induce browning of adipocyte. We observed that cells incubated with NO-releasing nanomatrix gel induces brown-like adipocytes in vitro. From these results, we hypothesize that SubQ administration of a NO-releasing nanomatrix gel is a novel therapeutic strategy to treat age-related metabolic dysfunction by promoting browning of adipocytes. To test the hypothesis; in the aim 1, we will determine the effect of subcutaneous (SubQ) administration of a NO- releasing nanomatrix gel on obesity and insulin resistance in aged mice; in the aim 2, we will elucidate the mechanisms by which NO-releasing nanomatrix gel enhances “browning” AT. Completion of these aims will provide a novel strategy to treat age-associated obesity and cardiometabolic diseases.