Adipose T cell microRNAs (miRs) regulate macrophage function during obesity

摘要 在过去的20年里，肥胖在美国和世界范围内的流行已经达到了流行病的程度 比例。肥胖是一个非常强大的健康决定因素，促进发展和进展， 几种代谢疾病、胰岛素抵抗和慢性炎症。高脂饮食（HFD）消耗 与肥胖的发展正相关。T细胞在发育早期浸润脂肪组织 肥胖症（在巨噬细胞流入之前），并强烈涉及炎症相关的启动 肥胖症在人类和小鼠中，肥胖脂肪组织中的巨噬细胞丰度增加， 出现M1（促炎）或M2（抗炎）表型。肥胖进展期间 初始和活化T细胞的microRNA（miRs）的差异表达表明它们在T细胞免疫中的重要性。 效应子（Teff）功能。此外，众所周知，miRs广泛调节脂肪细胞发育， 功能我们注意到T细胞稳态扩张和巨噬细胞丰度和表型的变化， 与喂食正常饮食（ND）的小鼠相比，喂食HFD的小鼠的脂肪组织。具体来说，我们的初步数据 表明HFD下调脂肪驻留T细胞miR-10a、-125b和-1247，并模拟miR的体内表达。 逆转与肥胖相关的代谢标志物的表达并调节巨噬细胞丰度。 基于严格性和初步数据，我们的中心假设是T细胞miR-10a，-125b和1247是 对于调节饮食诱导的脂肪细胞、T细胞和巨噬细胞之间的串扰至关重要 肥胖为了支持这一前提，我们将测试脂肪T细胞miRs是否在饮食诱导的肥胖中起关键作用。 肥胖（DIO）（目标1）;确定DIO中T细胞miR下调的机制（目标2）;确定 脂肪T细胞miR是否介导DIO中的巨噬细胞功能（目的3）。我们将首次探索 居民脂肪组织来源T细胞miR如何改变代谢功能和肥胖检验这一假设将 提供对T细胞miR、T细胞扩增和巨噬细胞之间相互作用的更深入理解 和脂肪组织微环境中的脂肪细胞功能，这可以允许有效的预防和 肥胖和代谢功能障碍的治疗选择。

ABSTRACT Over the past 20 years, the prevalence of obesity in the United States and worldwide has reached epidemic proportions. Obesity is a very powerful health determinant that facilitates the development and progression of several metabolic diseases, insulin resistance and chronic inflammation. High fat diet (HFD) consumption positively correlates with development of obesity. T cells infiltrate adipose tissue during the early development of obesity (prior to macrophage influx) and are strongly implicated in the initiation of inflammation associated with obesity. In both humans and mice, macrophage abundance increases in obese adipose tissue and can develop either M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes. During obesity progression differential expression of microRNAs (miRs) by naive and activated T cells suggests their importance in T cell effector (Teff) functions. Further, it is well established that miRs extensively regulate adipocyte development and function. We noticed T cell homeostatic expansion and changes in macrophage abundance and phenotype in adipose tissue of HFD fed mice compared to those fed a normal diet (ND). Specifically, our preliminary data indicates that HFD downregulates adipose resident T cell miRs-10a, -125b and -1247 and mimics miRs' in-vivo reversal of the expression of metabolic markers associated with obesity and modulates macrophage abundance. Based on strong rigor and preliminary data, our central hypothesis is that T cell miRs-10a, -125b and 1247 are essential for regulating crosstalk between adipocytes, T cells and macrophages during diet-induced obesity. To support this premise, we will test whether adipose T cell miRs play a crucial role in diet-induced obesity (DIO) (Aim 1); identify the mechanisms by which T cell miRs are downregulated in DIO (Aim 2); determine whether adipose T cell miRs mediate macrophage function in DIO (Aim 3). For the first time, we will explore how resident adipose tissue-derived T cell miRs alter metabolic function and obesity. Testing this hypothesis will provide an enhanced understanding on interactions between T cell miRs, T cell expansion, and macrophage and adipocyte function in the adipose tissue microenvironment that may allow for effective prevention and treatment options for obesity and metabolic dysfunction.