Harnessing macrophage lysosomal lipid metabolism in obesity-associated diseases

项目总结/摘要 肥胖相关代谢紊乱，包括胰岛素抵抗、2型糖尿病和非酒精性脂肪肝 疾病，被认为是由于脂质介导的免疫反应导致的低度非感染性炎症。 细胞活化，特别是巨噬细胞。然而，很明显，关注巨噬细胞 炎症信号传导过于简单化，无法解释炎症信号传导增加与炎症反应之间的复杂关系。 免疫细胞向代谢组织的募集和疾病发病机制。脂肪中巨噬细胞的表型 组织和肝脏证实了在饮食诱导的肥胖症中溶酶体脂质代谢程序的诱导， 这表明巨噬细胞向脂质超载组织的募集本质上可能是补偿性的。如果是这样， 增强巨噬细胞中脂质水解和代谢的细胞内在程序应该具有 有益的代谢作用。在初步的工作中，我们发现巨噬细胞TFEB的过度表达， 溶酶体和脂肪酸氧化基因的转录调节因子，增强巨噬细胞的能力， 在体外代谢脂质，在体内改善饮食诱导的代谢功能障碍，可能是因为 减少脂肪组织的脂肪酸释放。在这份提案中，我们将调查后果， 不同巨噬细胞亚群中激活巨噬细胞溶酶体脂质代谢的机制 影响肥胖引起的代谢功能障碍和脂肪肝疾病。在目标1中，我们将探讨TFEB的作用 脂肪组织巨噬细胞（ATM）在调节肥胖症脂肪组织和全身代谢功能中的作用。 这包括评估TFEB对富含脂质的外泌体和死亡脂肪细胞的代谢处理的影响 在冠状结构中发现。我们在小鼠中的发现也将在人类中得到证实， 确定ATM中溶酶体脂质代谢增加是否与代谢正常或代谢异常相关 异常肥胖在Aim-2中，我们将利用独特的遗传模型来确定TFEB对肝脏的影响。 在饮食诱导的脂肪变性和纤维化中，常驻枯否细胞与募集的单核细胞衍生的巨噬细胞。采取 总之，该提议将检验巨噬细胞溶酶体脂质降解的诱导- 通过TFEB的线粒体脂肪酸氧化基因网络将增强巨噬细胞脂质处理， 可以用来治疗肥胖相关的胰岛素抵抗和脂肪肝。

Project Summary / Abstract Obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease, are thought to be caused by low-grade non-infectious inflammation as a result of lipid-mediated immune cell activation, particularly macrophages. However, it has become clear that focusing on macrophage inflammatory signaling is overly simplistic and fails to explain the complex relationship between increased immune cell recruitment to metabolic tissues and disease pathogenesis. Phenotyping of macrophages in adipose tissue and liver demonstrates induction of a lysosomal lipid metabolism program in diet-induced obesity, suggesting that macrophage recruitment to lipid-overloaded tissues might be compensatory in nature. If so, then enhancing a cell-intrinsic program of lipid hydrolysis and metabolism in macrophages should have beneficial metabolic effects. In preliminary work, we show that overexpression of macrophage TFEB, a master transcriptional regulator of lysosomal and fatty acid oxidation genes, enhances the ability of macrophages to metabolize lipids in vitro and ameliorates diet-induced metabolic dysfunction in vivo, presumably because of reduced fatty acid release from adipose tissue. In this proposal, we will investigate the consequences and mechanisms by which activating macrophage lysosomal lipid metabolism in distinct macrophage subsets impacts obesity-induced metabolic dysfunction and fatty liver disease. In Aim-1, we will explore the role of TFEB in adipose tissue macrophages (ATM) in regulating adipose tissue and systemic metabolic function in obesity. This includes assessing TFEB’s effects on the metabolic handling of lipid-rich exosomes and dying adipocytes found in crown-like structures. Our findings in mice will also be confirmed in a human population where we will determine if increased lysosomal lipid metabolism in ATM associates with metabolically normal or metabolically abnormal obesity. In Aim-2, we will utilize unique genetic models to determine the impact of TFEB in liver resident Kupffer cells vs. recruited monocyte-derived macrophages on diet-induced steatosis and fibrosis. Taken together, this proposal will test the hypothesis that induction of a macrophage lysosomal lipid degradation- mitochondrial fatty acid oxidation gene network via TFEB will enhance macrophage lipid handling and could be leveraged to treat obesity-associated insulin resistance and fatty liver disease.