Interleukin-10 Signaling in Adipose Tissue Thermogenesis and Energy expenditure

项目说明 驻留在脂肪组织中的免疫系统的细胞类型被认为是至关重要的 代谢动态平衡的调节器。肥胖引起的脂肪组织慢性炎症与 代谢异常。因此，人们普遍认为抗炎因子有益于 胰岛素抵抗和糖尿病的领域。出乎意料的是，我们发现白介素10(IL-10)的消融具有抗 小鼠炎症信号改善胰岛素敏感性和糖耐量，保护饮食诱导 肥胖，并引起白色脂肪组织的褐变。这种表型与线粒体增多有关。 尽管食物消费增加，但呼吸和能量消耗仍在增加。野生型骨重建 骨髓进入IL-10基因敲除小鼠逆转了生热表型，表明造血起源于 IL-10信号调节脂肪组织功能。IL-10受体(IL-10R)在成熟脂肪细胞中高表达 使用反义寡核苷酸急性敲除Iwat特异性的IL10R可降低脂肪质量和 增加生热作用。IL-10处理可直接拮抗细胞内致热基因的表达 自主的方式。此外，全基因组转座酶可及染色质(ATAC)-seq的检测 和rna-seq证实了IL-10通过改变染色质来抑制产热基因的转录。 关键增强子和启动子区域的配置。这些发现确认IL-10轴是一种新的 脂肪组织中的产热转录程序，并挑战关于 肥胖背景下免疫和炎症信号与脂肪组织功能之间的联系。至 进一步验证脂肪特异性IL10R直接感知微环境中IL-10的假设以限制 脂肪的生热作用，我提出了两个相互关联的目标来研究i)代谢的后果 小鼠脂肪细胞特异性消融IL-10R的研究及II)IL-10抑制生热作用的机制 基因的体外转录和体内转录。该提案详细说明了一项为期五年的综合计划，该计划包括两年 指导培训计划(K99阶段)，然后是针对我的三年独立计划(R00阶段) 发展成为独立的学术科学研究事业。我有丰富的学习经验 免疫-脂肪相互作用和代谢性疾病，并计划将我的科学培训扩展到全基因组 指导阶段的测序和数据分析。我将在导师的指导下实现我的项目目标 我的顾问，国际公认的脂代谢专家Peter Tontonoz博士和Stephen博士 斯梅尔、Karen Reue和Orian Shirihai将担任我的主要顾问，提供相关的科学 良师益友和职业指导。总体而言，这项提议旨在推进我在关键科学领域的培训， 培养关键技能(撰写拨款、演示文稿、实验室管理等)，成为全面发展的 科学研究人员，并培养我过渡到一个独立的教员职位，在那里我将建立一个 跨学科研究计划侧重于肥胖症和代谢紊乱的机制。

PROJECT DESCRIPTION Cell types of the immune system residing within adipose tissue have been postulated to act as critical regulators of metabolic homeostasis. Obesity-induced chronic inflammation in adipose tissue is associated with metabolic abnormalities. It has therefore been widely assumed that anti-inflammatory factors are beneficial in areas of insulin resistance and diabetes. Unexpectedly, we find that ablation of interleukin-10 (IL-10) anti- inflammatory signaling in mice improves insulin sensitivity and glucose tolerance, protects against diet-induced obesity, and elicits browning of white adipose tissue. This phenotype is associated with increased mitochondrial respiration and energy expenditure despite increased food consumption. Reconstitution of wild-type bone marrow into IL-10 knockout mice reversed the thermogenic phenotype, pointing to a hematopoietic origin of the IL-10 signal regulating adipose tissue function. IL-10 receptor (IL10R) is highly expressed in mature adipocytes and iWAT-specific acute knockdown of IL10R using antisense oligonucleotide decreases fat mass and increases thermogenesis. IL-10 treatment directly antagonizes the expression of thermogenic genes in a cell autonomous manner. Furthermore, genome-wide Assay for Transposase-Accessible Chromatin (ATAC)-seq and RNA-seq demonstrated that IL-10 represses the transcription of thermogenic genes by altering chromatin configuration at key enhancer and promoter regions. These findings identify IL-10 axis as a novel regulator of a thermogenic transcriptional program in adipose tissue and challenge the conventional assumptions regarding the links between immune and inflammatory signaling and adipose tissue function in the setting of obesity. To further test the hypothesis that adipose-specific IL10R directly senses IL-10 in the microenvironment to limit adipose thermogenesis, I have proposed two interrelated aims to examine i) metabolic consequences of adipocyte-specific ablation of IL10R in mice, and ii) mechanisms underlying IL-10 inhibition of thermogenic gene transcription in vitro and in vivo. The proposal details a five-year integrated plan consisting of a two-year of mentored training program (K99 Phase) followed by a three-year independent program (R00 Phase) for my development into an independent academic science research career. I have significant experience studying immune-adipose interaction and metabolic diseases and plan to extend my scientific training in genome-wide sequencing and data analysis during the mentored phase. I will achieve my project goals with mentorship from my advisor, Dr. Peter Tontonoz, an internationally recognized expert in lipid metabolism, and Drs. Stephen Smale, Karen Reue, and Orian Shirihai who will serve as my key advisors to provide relevant scientific mentorship and career guidance. Overall, the proposal is designed to advance my training in key scientific areas, develop critical skills (grant-writing, presentation, lab management, and others) to become a well-rounded scientific investigator, and foster my transition to an independent faculty position where I will setup an interdisciplinary research program focused on mechanisms of obesity and metabolic disorders.