Harnessing macrophage lysosomal lipid metabolism in obesity-associated diseases

项目摘要/摘要 肥胖相关的代谢紊乱，包括胰岛素抵抗、2型糖尿病和非酒精性脂肪肝 疾病，被认为是由脂质介导的免疫引起的低级别非感染性炎症引起的 激活细胞，特别是巨噬细胞。然而，关注巨噬细胞已经变得很明显 炎症信号过于简单，无法解释两者之间的复杂关系 免疫细胞向代谢组织募集与疾病发病机制。脂肪组织中巨噬细胞的表型分析 组织和肝脏显示，在饮食诱导的肥胖中，溶酶体脂代谢程序被诱导。 这表明巨噬细胞在脂质过载的组织中的募集可能在本质上是代偿的。如果是这样，那么 在巨噬细胞中增强细胞固有的脂质水解和代谢程序应该有 有益的新陈代谢作用。在初步工作中，我们发现巨噬细胞TFEB过表达，这是一种主要的 溶酶体和脂肪酸氧化基因的转录调节，增强巨噬细胞的能力 在体外代谢脂质并在体内改善饮食诱导的代谢功能障碍，推测是因为 减少脂肪组织中的脂肪酸释放。在这项提案中，我们将调查后果并 不同巨噬细胞亚群激活巨噬细胞溶酶体脂代谢的机制 影响肥胖引起的代谢功能障碍和脂肪肝疾病。在AIM-1中，我们将探索TFEB的作用 在脂肪组织中，巨噬细胞(ATM)在肥胖中调节脂肪组织和全身代谢功能。 这包括评估TFEB对富含脂肪的外切体和死亡脂肪细胞代谢处理的影响 发现于冠状结构中。我们在老鼠身上的发现也将在人类群体中得到证实，在那里我们将 确定ATM患者溶酶体脂代谢增加是否与代谢正常或代谢有关 不正常的肥胖。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 常驻Kupffer细胞与单核细胞来源的巨噬细胞在饮食诱导的脂肪变性和纤维化中的招募。已被占用 总而言之，这项提议将检验这样一个假设，即诱导巨噬细胞溶酶体脂降解- 通过TFEB的线粒体脂肪酸氧化基因网络将增强巨噬细胞的脂质处理和 可用于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.