Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Biomater Sci. 2021 Jan 21;9(2):506-518. doi: 10.1039/d0bm01142h. Epub 2020 Nov 17.
Obesity is associated with systemic inflammation due to macrophage accumulation in adipose tissue (AT). AT macrophages are, therefore, a target for therapeutics to modulate inflammation and prevent comorbidities. Because inflammatory processes have pleiotropic effects throughout the body and are intertwined with metabolic axes, systemic anti-inflammatory therapies are often harmful. We report that targeting AT macrophages using dextran nanocarriers radically alters the pharmacology of anti-inflammatory glucocorticoids, uncoupling the metabolic axis in obese mice. Following a single treatment, expression of inflammatory mediators and markers of inflammatory macrophages decreased with a nearly 20-fold higher potency compared with free drug. As a result, long-term treatment resulted in potent fat mobilization, AT reduction, weight loss, improved glucose tolerance, and altered AT gene expression profiles that led to elevated liver stress. Two weeks after treatment ceased, gene expression of inflammatory mediators in AT remained lower than obese controls, while gene expression related to metabolic function improved. These data demonstrate that nanocarriers show potential for amelioration of obesity-related AT inflammation and metabolic dysfunction, highlighting an important opportunity for nanomedicine to impact chronic metabolic disorders with complex and poorly understood etiology.
肥胖与脂肪组织（AT）中巨噬细胞积累引起的全身炎症有关。因此，AT 巨噬细胞是治疗炎症和预防合并症的药物靶点。由于炎症过程在全身具有多效性，并与代谢轴交织在一起，全身抗炎治疗往往是有害的。我们报告称，使用葡聚糖纳米载体靶向 AT 巨噬细胞可从根本上改变抗炎糖皮质激素的药理学，使肥胖小鼠的代谢轴解偶联。单次治疗后，与游离药物相比，炎症介质和炎症巨噬细胞标志物的表达减少，效力高出近 20 倍。结果，长期治疗导致脂肪动员、AT 减少、体重减轻、葡萄糖耐量改善，以及改变 AT 基因表达谱，导致肝应激升高。治疗停止两周后，AT 中炎症介质的基因表达仍低于肥胖对照组，而与代谢功能相关的基因表达则得到改善。这些数据表明，纳米载体具有改善肥胖相关 AT 炎症和代谢功能障碍的潜力，突出了纳米医学在影响具有复杂和理解不足病因的慢性代谢疾病方面的重要机会。
