ADIPOSE TISSUE MACROPHAGE PHENOTYPE AND FUNCTION

描述（由申请人提供）：脂肪组织的发育、代谢和内分泌功能对于脂肪细胞中脂质的有效储存和正常的全身代谢至关重要。肥胖改变脂肪组织功能，损害甘油三酯在脂肪细胞中的有效储存，导致脂质异位沉积和非脂肪组织的代谢损伤。脂肪组织巨噬细胞（ATMs）通过其炎症功能参与肥胖诱导的脂肪细胞功能障碍和并发症的发展，包括2型糖尿病、非酒精性脂肪性肝病和血脂异常。该基金资助的研究表明，肥胖导致肥胖啮齿动物和人类脂肪组织中巨噬细胞的积累，脂肪组织巨噬细胞在很大程度上促进了局部和全身肥胖诱导的炎症，脂肪组织中巨噬细胞的含量与肥胖相关的代谢紊乱密切相关。调节脂肪组织发育和代谢的巨噬细胞的非炎症或营养功能尚未得到很好的表征。在其他组织中，包括骨、中枢神经系统和肝脏，巨噬细胞通过复杂的旁分泌回路在实质细胞的发育和维持中发挥重要作用。我们最近的一些观察表明，脂肪细胞和atm之间存在类似的通信。在目前的资助期内，我们发现脂肪细胞脂解迅速导致ATM积累，肥胖个体脂肪组织中巨噬细胞的消耗增加了基础脂解，ATM是肥胖脂肪组织中胰岛素样生长因子-1 （Igf1）和脂蛋白脂肪酶（Lpl）的主要来源，令人惊讶的是，肥胖而不是诱导ATM中的经典炎症程序激活脂质摄取和溶酶体生物生成程序。从这些数据中出现了atm的二分图，其中它们对脂肪细胞和脂肪组织功能的作用是它们的炎症和营养功能的平衡。为了更全面地了解ATM的功能，我们提出了三个目标，重点阐明营养相互作用的各个方面：1)研究脂肪分解在肥胖中ATM的慢性募集和积累中的作用；2)确定ATM溶酶体和自噬在ATM功能和脂肪组织代谢中的作用；3)表征ATM衍生的IGF-1和LPL在脂肪组织发育和代谢中的作用。实现本提案的目标将确定ATM积累和功能所需的关键过程和分子。成功也将为脂肪组织生理学提供重要的见解，并通过确定调节脂肪组织中巨噬细胞积聚和功能的分子机制，确定减少肥胖诱导的脂肪细胞功能障碍及其伴随并发症的潜在新策略。

DESCRIPTION (provided by applicant): Adipose tissue development, metabolism and endocrine function are essential for the efficient storage of lipids in adipocytes and for normal systemic metabolism. Obesity alters adipose tissue function and impairs the efficient storage of triglycerides in adipocytes, leading to ectopic deposition of lipids and metabolic impairment in non-adipose tissues. Adipose tissue macrophages (ATMs) through their inflammatory function have been implicated in the development of obesity-induced adipocyte dysfunction and complications, including type 2 diabetes, non-alcoholic fatty liver disease and dyslipidemia. Studies funded by this grant have revealed that obesity leads to the accumulation of macrophages in adipose tissue of obese rodents and humans, that adipose tissue macrophages contribute substantially to local and systemic obesity- induced inflammation and that the macrophage content of adipose tissue is tightly correlated with metabolic derangements associated obesity. The non-inflammatory or trophic functions of macrophages that modulate adipose tissue development and metabolism have been less well characterized. In other tissues, including bone, the central nervous system and liver, resident macrophages through complex paracrine loops play essential roles in the development and maintenance of parenchymal cells. Some of our recent observations suggest similar communication exists between adipocytes and ATMs. During the current grant period, we found that adipocyte lipolysis rapidly leads to ATM accumulation, that depletion of macrophages in adipose tissue from obese individuals increases basal lipolysis, that ATMs are the primary source of both insulin-like growth factor-1 (Igf1) and lipoprotein lipase (Lpl) in obese adipose tissue and surprisingly that obesity rather then inducing a classical inflammatory program in ATMs activates a program of lipid uptake and lysosome biogenesis. From these data emerge a dichotomous picture of ATMs in which their action on adipocytes and adipose tissue function is the balance of their inflammatory and trophic functions. In an effort to provide a more complete picture of ATM function we propose three aims focused on elucidating aspects of the trophic interactions: 1) To study the role of lipolysis in the chronic recruitment and accumulation of ATMs in obesity 2) To determine the role of ATM lysosomes and autophagy in function ATMs and adipose tissue metabolism 3) To characterize the role of ATM-derived IGF-1 and LPL in adipose tissue development and metabolism. Achieving the goals of this proposal will identify critical processes and molecules required for ATM accumulation and function. Success will also provide important insights into adipose tissue physiology, and by identifying the molecular mechanisms that regulate macrophage accumulation and function in adipose tissue, identify potential novel strategies to reduce obesity-induced adipocyte dysfunction and its attendant complications. PUBLIC HEALTH RELEVANCE: Obesity is defined by the expansion of adipose tissue and is a leading cause of type 2 diabetes, non-alcoholic fatty liver disease and dyslipidemia. Understanding how adipose tissue macrophages contribute to adipose tissue health and dysfunction will identify therapeutic strategies to combat obesity-associated diseases.