Novel mechanisms regulating adipose tissue function in health and disease

调节健康和疾病中脂肪组织功能的新机制

• 批准号: 10736765
• 负责人: Elisabetta Mueller
• 金额: $ 47.12万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736765
• 关键词: ADORA2A gene; Ablation; Adenosine; Adipocytes; Adipose tissue; Affect; Aging; Animal Model; Biology; Calories; Cell secretion; Cells; Chromatin; Conditioned Culture Media; Consumption; Cues; Data; Development; Disease; Energy Intake; Epigenetic Process; Equilibrium; Expenditure; Fatty acid glycerol esters; Genes; Genetic Transcription; HSF1; Health; Heat shock factor; Heat-Shock Response; Homeostasis; Human; Knockout Mice; Knowledge; Laboratories; Learning; Link; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Molecular; Molecular Target; Mus; Nutrient availability; Nutritional; Obesity; Output; Pathologic; Pathway interactions; Physiological; Process; Publishing; Reagent; Regulation; Risk Factors; Role; Signal Transduction; Stimulus; Stress; Techniques; Technology; Temperature; Thermogenesis; Time; Tissue Expansion; Tissues; Transgenic Animals; Work; adipocyte biology; chromatin remodeling; cofactor; combat; energy balance; exosome; fighting; genome-wide; histone demethylase; innovation; insight; interest; lipidomics; new therapeutic target; next generation sequencing; novel; novel strategies; novel therapeutic intervention; novel therapeutics; promoter; proteotoxicity; response; therapeutic target; tool; treatment strategy

PROJECT SUMMARY/ABSTRACT Excessive adipose tissue expansion causes obesity, a major risk factor for the development of metabolic disease. Three types of fat cells exist -white, brown and beige- involved in maintaining the balance between calories hoarded and those consumed. It has been recently suggested that increasing energy dissipation via the induction of thermogenesis in brown and beige adipocytes could represent a strategy to combat metabolic disease; however, at the present time, our understanding of the key targetable regulators involved in this process is still limited. My laboratory has identified the heat shock factor HSF1 as a novel transcriptional regulator of thermogenesis and has preliminary evidence demonstrating that HSF1 regulates histone demethylases, that obesity is associated with low levels of HSF1 and that ablation of HSF1 in fat leads to metabolic dysfunction. Based on this knowledge, we propose to determine how fat tissue is epigenetically reprogrammed in obese states and identify new molecular mechanisms controlling adipose tissue biology through the analysis of novel upstream regulators and downstream effectors of HSF1 in fat. The results of our studies will identify novel regulatory mechanisms controlling adipose tissue biology and specific epigenetic signatures contradistinctive of obese fat, identify HSF1 is a novel molecular link between extrinsic stimuli and transcriptional and epigenetic re- programming of adipose tissue, and a possible new therapeutic target for the treatment of metabolic dysfunction. To perform the studies outlined we will take advantage of unique fat specific HSF1- and adenosine receptor A2A knock-out mice generated in our laboratory and of techniques and reagents generated over the years and more innovative ones. In Aim 1 will identify novel chromatin signatures in adipose tissues associated with obesity and will assess the role of HSF1 in the epigenetic control of adipose tissue biology and homeostasis; in Aim 2 we will characterize novel regulators of adipocyte biology through the identification of new molecular targets of HSF1 in adipocytes, using state-of-the-art next generation sequencing technologies, in addition to candidate approaches; in Aim 3 we will identify novel pathways regulating innate thermogenesis in fat cells. We expect that the studies outlined will illuminate novel mechanisms that control energy balance in physiological and pathological metabolic states and will define new approaches to increase energy dissipation and combat metabolic disease.

项目摘要/摘要 过度脂肪组织扩张会导致肥胖，这是代谢发展的主要危险因素 疾病。存在三种类型的脂肪细胞 - 白色，棕色和米色与维持之间的平衡有关 卡路里ho积和消耗的卡路里。最近有人提出，通过 在棕色和米色脂肪细胞中诱导热生成可以代表对抗代谢的策略 疾病;但是，目前，我们对参与此过程的主要目标监管机构的理解 仍然有限。我的实验室已将热休克因子HSF1确定为新型的转录调节剂 热发生并具有初步证据，表明HSF1调节组蛋白脱甲基酶，即 肥胖与低水平的HSF1有关，而HSF1在脂肪中的消融会导致代谢功能障碍。 基于这些知识，我们建议确定在肥胖中如何表观遗传编程的脂肪组织 状态并通过分析新的分析来控制控制脂肪组织生物学的新分子机制 脂肪中HSF1的上游调节剂和下游效应子。我们的研究结果将确定新颖 控制脂肪组织生物学和特定表观遗传学特征的调节机制矛盾 肥胖脂肪，识别HSF1是外在刺激与转录和表观遗传学之间的新分子联系 脂肪组织的编程，以及用于治疗代谢功能障碍的新治疗靶点。 为了进行概述的研究，我们将利用独特的脂肪特异性HSF1和腺苷受体A2A 在我们的实验室产生的敲除小鼠以及多年来产生的技术和试剂 创新的。在AIM 1中，将确定与肥胖和肥胖和 将评估HSF1在脂肪组织生物学和稳态的表观遗传控制中的作用；在目标2中我们 将通过鉴定HSF1的新分子靶标表征脂肪细胞生物学的新型调节剂 在脂肪细胞中，除了候选人外，还使用最先进的下一代测序技术 方法；在AIM 3中，我们将确定调节脂肪细胞先天生热的新途径。 我们期望所述的研究将阐明控制生理能量平衡的新型机制 和病理代谢状态，并将定义增加能量耗散和战斗的新方法 代谢疾病。