Immune pathways in adipose thermogenesis

脂肪产热中的免疫途径

基本信息

批准号：
10019525
负责人：
PETER J TONTONOZ
金额：
$ 45.71万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2019-09-16 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10019525
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 Diet 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 genome-wide improved insulin sensitivity knock-down lipid metabolism novel promoter receptor response single-cell RNA sequencing targeted treatment transcription factor

项目摘要

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中起着核心作用，脂肪细胞失调功能是代谢综合征的发病机理的基础。识别和表征与脂肪细胞生物学有关的重要蛋白质，包括PPARγ，TLE3和以及 PSPC1。 IL10。系统性代谢，脂肪生热以及免疫细胞和脂肪细胞之间的crostall 刺激脂肪组织热发生的调节途径广泛的表征，但支出的限制仍然很差。发现脂肪细胞中通过STAT3发出的IL10信号调节热基因表达和能量消耗。响应差异，肥胖和衰老。米色脂肪细胞中的肾上腺素能信号传导，并降低了热基因上ATF和C/C/EBPβ的占用基因启动子。反义寡核苷酸（ASOS）可防止饮食诱导的肥胖症，表明脂肪IL10 轴可能是针对治疗的。产生并接收影响代谢的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由IL10调节热生成的种群。 IL-10信号在脂质组织中的脂质存储和热发生中的作用。 IL-10的生热的转录调制的基础机制。脂肪组织居住的免疫细胞在IL10调节热发生中的作用。