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肪的有效储存和正常的全身新陈代谢是必不可少的。肥胖改变了脂肪组织的功能，损害了脂肪细胞中甘油三酯的有效储存，导致非脂肪组织中脂质的异位沉积和代谢障碍。脂肪组织巨噬细胞通过其炎症功能参与肥胖引起的脂肪细胞功能障碍和并发症的发生，包括2型糖尿病、非酒精性脂肪性肝病和血脂异常。由这笔赠款资助的研究表明，肥胖会导致肥胖啮齿动物和人类脂肪组织中巨噬细胞的积聚，脂肪组织巨噬细胞对肥胖引起的局部和全身炎症有很大贡献，脂肪组织中的巨噬细胞含量与肥胖相关的代谢紊乱密切相关。巨噬细胞调节脂肪组织发育和代谢的非炎性或营养功能还没有得到很好的描述。在其他组织中，包括骨、中枢神经系统和肝脏，驻留的巨噬细胞通过复杂的旁分泌环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，脂肪细胞和自动取款机之间存在类似的通讯。在目前的资助期间，我们发现脂肪细胞脂解迅速导致ATM积聚，肥胖者脂肪组织中巨噬细胞的耗尽增加了基础脂解，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，肥胖而不是在ATM中引发经典的炎症程序激活了脂质摄取和溶酶体生物生成的程序。从这些数据中可以看出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功能和营养功能的平衡。为了更全面地了解ATM的功能，我们提出了三个目标，着重于阐明营养相互作用的各个方面：1)研究脂肪分解在肥胖症患者ATM慢性募集和积聚中的作用；2)确定ATM溶酶体和自噬在功能ATM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。实现这项提案的目标将确定自动柜员机积累和运行所需的关键过程和分子。该研究的成功还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聚集和功能的分子机制，确定潜在的新策略，以减少肥胖引起的脂肪细胞功能障碍及其伴随的并发症。 公共卫生相关性：肥胖的定义是脂肪组织的扩张，是2型糖尿病、非酒精性脂肪性肝病和血脂异常的主要原因。了解脂肪组织巨噬细胞如何促进脂肪组织的健康和功能障碍，将确定与肥胖相关疾病作斗争的治疗策略。

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.