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

摘要 在过去的20年里，肥胖症在美国和世界范围内的流行已经达到了流行病 比例。肥胖是一个非常强大的健康决定因素，它促进了糖尿病的发展和进展 几种代谢性疾病、胰岛素抵抗和慢性炎症。高脂饮食(HFD)消费 与肥胖的发生呈正相关。T细胞在发育早期的脂肪组织中的渗透 肥胖(在巨噬细胞涌入之前)，并与炎症的启动密切相关 与肥胖有关。在人类和小鼠中，肥胖脂肪组织中巨噬细胞的丰度增加，并可以 形成M1(促炎)或M2(抗炎)表型。在肥胖进展过程中 幼稚T细胞和活化T细胞表达microRNAs(MiRs)的差异表明它们在T细胞中的重要性 效应器(TEF)函数。此外，众所周知，miRs广泛调节脂肪细胞的发育和 功能。我们注意到T细胞的稳态扩张以及巨噬细胞丰度和表型的变化。 饲喂HFD小鼠的脂肪组织与饲喂正常饮食(ND)的小鼠进行比较。具体地说，我们的初步数据 表明HFD下调脂肪驻留T细胞miRs-10a、-125b和-1247，并在体内模拟miRs 逆转与肥胖相关的代谢标记物的表达并调节巨噬细胞的丰度。 基于强大的严谨性和初步数据，我们的中心假设是T细胞miRs-10a、-125b和1247是 在饮食诱导过程中调节脂肪细胞、T细胞和巨噬细胞之间的串扰 肥胖。为了支持这一前提，我们将测试脂肪T细胞miRs在饮食诱导中是否发挥关键作用 肥胖(DIO)(目标1)；确定DIO中T细胞miRs下调的机制(目标2)；确定 脂肪T细胞miRs是否在DIO中介导巨噬细胞功能(目标3)。第一次，我们将探索 居民脂肪组织衍生的T细胞MIR如何改变代谢功能和肥胖。检验这一假说将 加深对T细胞miRs、T细胞扩增和巨噬细胞之间相互作用的理解 和脂肪细胞在脂肪组织微环境中的功能，这可能允许有效地预防和 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.