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

• 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
• 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

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 属于脂肪组织内的免疫系统的细胞类型已被张贴起到至关重要的作用 代谢稳态的调节剂。肥胖引起的脂肪组织中的慢性炎症与 代谢异常。因此，已广泛认为抗炎因子对 胰岛素抵抗和糖尿病区域。出乎意料的是，我们发现白介素10（IL-10）抗 - 小鼠的炎症信号传导可提高胰岛素敏感性和葡萄糖耐受性，可预防饮食诱导的 肥胖，并引起白脂肪组织的褐变。该表型与线粒体增加有关 呼吸和能量消耗增加了食物消耗。野生型骨骼的重建 骨髓进入IL-10敲除小鼠逆转了热表型，指向造血的起源 IL-10信号调节脂肪组织功能。 IL-10受体（IL10R）在成熟的脂肪细胞中高度表达 使用反义寡核苷酸的IL10R的IWAT特异性急性敲低降低了脂肪质量和 增加热生成。 IL-10处理直接拮抗细胞中热基因的表达 自主方式。此外，针对转座酶可访问的染色质（ATAC）-Seq的全基因组测定法 RNA-seq表明IL-10通过改变染色质再现了热基因的转录 钥匙增强子和启动子区域的配置。这些发现将IL-10轴确定为一个新的调节剂 脂肪组织中的热转录程序，并挑战有关传统假设 在肥胖症的情况下，免疫和炎症信号传导与脂肪组织功能之间的联系。到 进一步检验以下假设：脂肪特异性IL10R直接在微环境中感应IL-10 脂肪生热发生，我提出了两个相互关联的目的，以检查i）代谢后果 IL10R在小鼠中的脂肪细胞特异性消融和II）IL-10抑制基础的机制 基因在体外和体内转录。该提案详细介绍了一个五年的综合计划，包括两年 指导培训计划（K99阶段），然后为我的三年独立计划（R00阶段） 发展成为独立的学术科学研究职业。我有丰富的学习经验 免疫 - 辅助剂相互作用和代谢疾病，并计划扩展我在全基因组方面的科学培训 在纪念阶段进行测序和数据分析。我将通过从 我的顾问彼得·顿托诺兹（Peter Tontonoz）博士是脂质代谢方面的国际认可专家，博士。斯蒂芬 Smale，Karen Reue和Orian Shirihai将担任我的主要顾问，以提供相关的科学 识别和职业指导。总体而言，该提案旨在推进我在关键科学领域的培训， 发展关键技能（赠款，演示，实验室管理等），成为一个全面的 科学研究者，并促进我过渡到独立教师职位，我将在其中设置 跨学科研究计划的重点是肥胖和代谢性疾病的机制。