Interleukin-10 Signaling in Adipose Tissue Thermogenesis and Energy expenditure

脂肪组织产热和能量消耗中的 IL-10 信号传导

基本信息

批准号：
9984687
负责人：
Prashant Rajbhandari
金额：
$ 24.81万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-15 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9984687
关键词：
Ablation Acute Adipocytes Adipose tissue Adrenergic Agents Aging Animal Model Animals Anti-inflammatory Antisense Oligonucleotides Area Biogenesis Biological Biological Assay Biology Bone Marrow Brown Fat Cardiovascular Diseases Cells ChIP-seq Chromatin Chronic Data Data Analyses Development Diabetes Mellitus Diet Energy Metabolism Enhancers Epigenetic Process Equilibrium Faculty Fatty acid glycerol esters Fellowship Fostering Future Gene Expression Profile Genes Genetic Transcription Goals Grant Heart Diseases Hematopoietic Homeostasis Immune Immune system In Vitro Inflammation Inflammatory Insulin Resistance Interdisciplinary Study Interleukin-10 International Knockout Mice Link Lipid Mobilization Lipids Mediating Mentors Mentorship Metabolic Metabolic Diseases Metabolic syndrome Methodology Mitochondria Modeling Modification Mus Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Obesity Pathogenesis Pathologic Pathway interactions Phase Phenotype Play Positioning Attribute Process Promoter Regions Property Receptor Signaling Research Research Personnel Respiration Role STAT3 gene Science Signal Transduction Testing Therapeutic Thermogenesis Time Tissues Training Training Programs Transposase Vocational Guidance Writing age related base career cell type chemokine chromatin immunoprecipitation combat cytokine design experience experimental study food consumption genome-wide glucose tolerance improved in vivo insulin sensitivity interleukin-10 receptor knock-down lipid metabolism loss of function metabolic abnormality assessment novel programs public health relevance reconstitution response skills trait transcriptome transcriptome sequencing

项目摘要

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.

项目描述脂肪组织内免疫系统的细胞类型被认为起着至关重要的作用代谢稳态的调节因子与肥胖引起的脂肪组织慢性炎症有关。因此，人们普遍认为抗炎因子对代谢异常有益。出乎意料的是，我们发现白细胞介素 10 (IL-10) 的消融可以抗- 小鼠炎症信号改善胰岛素敏感性和葡萄糖耐量，防止饮食引起的肥胖，并引起白色脂肪组织褐变，这种表型与线粒体增加有关。尽管食物消耗增加，但呼吸和能量消耗仍然存在。将骨髓注入 IL-10 敲除小鼠体内可逆转生热表型，表明该细胞具有造血起源。 IL-10 信号调节脂肪组织功能 IL-10 受体 (IL10Rα) 在成熟脂肪细胞中高表达。使用反义寡核苷酸对 iWAT 特异性急性敲除 IL10Rα 可减少脂肪量和 IL-10 处理可直接拮抗细胞中生热基因的表达。此外，转座酶可及染色质 (ATAC)-seq 的全基因组测定。 RNA-seq 证明 IL-10 通过改变染色质来抑制生热基因的转录这些发现将 IL-10 轴确定为一种新型的调节子。脂肪组织中的产热转录程序并挑战有关的传统假设肥胖背景下免疫和炎症信号与脂肪组织功能之间的联系。进一步检验脂肪特异性 IL10Rα 直接感知微环境中的 IL-10 以限制的假设脂肪产热，我提出了两个相互关联的目标来检查 i) 的代谢后果小鼠中 IL10Rα 的脂肪细胞特异性消融，以及 ii) IL-10 抑制产热的机制该提案详细介绍了一个包含两年的五年综合计划。指导培训计划（K99 阶段），然后是为期三年的独立计划（R00 阶段）我有丰富的学习经验。免疫脂肪相互作用和代谢疾病，并计划扩展我在全基因组范围内的科学培训在指导阶段进行测序和数据分析，我将在指导下实现我的项目目标。我的导师 Peter Tontonoz 博士是一位国际公认的脂质代谢专家，还有 Stephen 博士。 Smale、Karen Reue 和 Orian Shirihai 将作为我的主要顾问，提供相关的科学知识总的来说，该提案旨在促进我在关键科学领域的培训，培养关键技能（资助写作、演示、实验室管理等），成为全面发展的人才科学研究员，并促进我过渡到独立教职职位，在那里我将建立一个跨学科研究项目侧重于肥胖和代谢紊乱的机制。