Immune pathways in adipose thermogenesis

脂肪产热中的免疫途径

• 批准号: 10460987
• 负责人: PETER J TONTONOZ
• 金额: $ 45.56万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460987
• 关键词: ATAC-seq; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic beta-Agonists; Affect; Aging; Antisense Oligonucleotides; Architecture; Binding Sites; Blood Vessels; CCAAT-Enhancer-Binding Proteins; Cell Fraction; Cells; ChIP-seq; Chromatin; DNA Modification Process; Data; Diabetes Mellitus; Dissection; Energy Metabolism; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Goals; Homeostasis; Host Defense; Immune; Individual; Interleukin-10; Intervention; Knockout Mice; Lipids; Lymphocyte; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Mus; Nucleic Acid Regulatory Sequences; Obesity; PPAR gamma; Pathogenesis; Pathway interactions; Physiological; Play; Population; Process; Production; Proteins; Public Health; Regulation; Regulatory Pathway; Role; STAT3 gene; Signal Pathway; Signal Transduction; Source; Thermogenesis; Tissues; Transgenic Organisms; activating transcription factor; adipocyte biology; cell type; chromatin remodeling; cohort; cytokine; diet-induced obesity; genome-wide; improved; insulin sensitivity; knock-down; lipid metabolism; novel; promoter; receptor; response; single-cell RNA sequencing; targeted treatment; transcription factor

Abstract Adipose tissue plays a central role in metabolic and energy homeostasis, and dysregulation of adipocyte function is fundamental to the pathogenesis of the metabolic syndrome. Our group has a track record of identifying and characterizing important proteins involved in adipocyte biology, including PPARγ, TLE3, and PSPC1. Recently, we uncovered a novel physiological regulator of adipose thermogenic activity: the cytokine IL10. This proposal builds upon this discovery to address important questions regarding the regulation of systemic metabolism, adipose thermogenesis, and the crosstalk between immune cells and adipocytes within adipose tissue depots. Regulatory pathways that stimulate adipose tissue thermogenesis have been extensively characterized, but the limiters of energy expenditure have remained poorly defined. We have discovered that IL10 signaling through STAT3 in adipocytes regulates thermogenic gene expression and energy expenditure. The IL10 receptor alpha (IL10Rα) is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Preliminary data indicate that IL-10 signaling inhibits beta- adrenergic signaling in beige adipocytes, and reduces the occupancy of ATF and C/EBPβ on thermogenic gene promoters. Moreover, inhibiting the expression of the IL10 receptor alpha (IL10Rα) in adipose tissue with antisense oligonucleotides (ASOs) is protective against diet-induced obesity, suggesting that the adipose IL10 axis might be targeted therapeutically. Here we propose to further define the specific cell types and tissues that produce and receive IL-10 signals affecting metabolism, to elucidate the mechanisms by which IL10 signaling regulates adipocyte gene expression, and to understand the roles of adipose tissue immune cell populations in the regulation of thermogenesis by IL10. Specific Aim 1 is to characterize the adipocyte-intrinsic role of IL-10 signaling in lipid storage and thermogenesis in adipose tissue. Specific Aim 2 is to define the mechanisms underlying transcriptional modulation of thermogenesis by IL-10. Specific Aim 3 is to delineate the role of adipose tissue-resident immune cells in the regulation of thermogenesis by IL10.

抽象的 脂肪组织在代谢和能量稳态以及脂肪细胞失调中发挥着核心作用 功能是代谢综合征发病机制的基础。我们的团队有以下记录 鉴定和表征脂肪细胞生物学中涉及的重要蛋白质，包括 PPARγ、TLE3 和 PSPC1。最近，我们发现了一种新型的脂肪产热活性生理调节剂：细胞因子 IL10。该提案建立在这一发现的基础上，旨在解决有关监管的重要问题 全身代谢、脂肪产热以及免疫细胞和脂肪细胞之间的串扰 脂肪组织库。刺激脂肪组织产热的调节途径已被研究 已被广泛描述，但能源消耗的限制因素仍然不明确。我们有 发现脂肪细胞中 IL10 信号通过 STAT3 调节产热基因表达 能量消耗。 IL10受体α（IL10Rα）在成熟脂肪细胞中高度富集并被诱导 应对分化、肥胖和衰老。初步数据表明 IL-10 信号传导抑制 β- 米色脂肪细胞中的肾上腺素信号传导，并减少 ATF 和 C/EBPβ 对产热的占据 基因启动子。此外，抑制脂肪组织中IL10受体α（IL10Rα）的表达 反义寡核苷酸 (ASO) 可预防饮食引起的肥胖，表明脂肪 IL10 轴可能是治疗的目标。在这里我们建议进一步定义特定的细胞类型和组织 产生和接收影响新陈代谢的 IL-10 信号，以阐明 IL10 的机制 信号传导调节脂肪细胞基因表达，并了解脂肪组织免疫细胞的作用 群体通过 IL10 调节生热作用。具体目标 1 是表征脂肪细胞固有的 IL-10 信号传导在脂肪组织脂质储存和生热作用中的作用。具体目标 2 是定义 IL-10 生热作用转录调节的潜在机制。具体目标 3 是描绘 脂肪组织驻留免疫细胞在 IL10 调节生热作用中的作用。