Interleukin-10 Signaling in Adipose Tissue Thermogenesis and Energy expenditure

项目描述 细胞类型的免疫系统驻留在脂肪组织已假定作为关键 代谢平衡的调节剂。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，抗炎因子在炎症反应中是有益的。 胰岛素抵抗和糖尿病领域。出乎意料的是，我们发现去除白细胞介素-10（IL-10）抗- 小鼠的炎症信号传导改善了胰岛素敏感性和葡萄糖耐量， 肥胖症和白色脂肪组织的elevant布朗宁。这种表型与增加的线粒体 呼吸和能量消耗，尽管增加了食物消耗。野生型骨重建 将IL-10基因敲除小鼠的骨髓注入IL-10基因敲除小鼠后， IL-10信号调节脂肪组织功能。IL-10受体在成熟脂肪细胞中高度表达 和使用反义寡核苷酸的IL 10 R β的iWAT特异性急性敲低降低了脂肪量， 增加产热作用。IL-10治疗直接拮抗细胞中产热基因的表达 自主的方式。此外，全基因组转座酶可降解染色质测定（ATAC）-seq 和RNA-seq证明IL-10通过改变染色质来抑制产热基因的转录 在关键的增强子和启动子区域的构型。这些发现将IL-10轴确定为一种新的调节因子， 脂肪组织中的产热转录程序，并挑战关于 免疫和炎症信号传导与肥胖背景下脂肪组织功能之间的联系。到 进一步检验脂肪特异性IL-10受体直接感知微环境中IL-10的假设， 脂肪产热，我提出了两个相互关联的目标，以检查i）代谢的后果， 小鼠中IL-10受体的脂肪细胞特异性消融，和ii）IL-10抑制产热的潜在机制， 体外和体内的基因转录。该提案详细说明了一项五年综合计划，包括一个两年期的 的指导培训计划（K99阶段），然后是一个为期三年的独立计划（R 00阶段），为我的 发展成为独立的学术科研事业。我有丰富的经验 免疫-脂肪相互作用和代谢疾病，并计划扩大我在全基因组方面科学训练 在指导阶段进行排序和数据分析。我将通过以下导师的指导实现我的项目目标： 我的导师Peter Tontonoz博士是国际公认的脂质代谢专家， Smale、Karen Reue和Orian Shirihai，他们将作为我的主要顾问， 辅导和职业指导。总的来说，这个提议旨在促进我在关键科学领域的训练， 发展关键技能（资助撰写、演示、实验室管理等），成为全面的人才 科学调查员，并促进我过渡到一个独立的教师职位，我将建立一个 跨学科的研究计划，侧重于肥胖和代谢紊乱的机制。

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.