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.

项目总结/摘要 过度的脂肪组织扩张导致肥胖，这是代谢性疾病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--它们参与维持 储存的卡路里和消耗的卡路里。最近有人提出，通过增加能量耗散， 在棕色和米色脂肪细胞中诱导产热可能代表对抗代谢的策略， 疾病;然而，目前，我们对参与这一过程的关键靶向调节剂的理解 仍然有限。我的实验室已经确定了热休克因子HSF 1作为一种新的转录调节因子， 生热，并有初步证据表明HSF 1调节组蛋白脱甲基酶， 肥胖与低水平的HSF 1有关，并且脂肪中HSF 1的消除导致代谢功能障碍。 基于这些知识，我们建议确定肥胖患者的脂肪组织是如何在表观遗传学上重新编程的。 状态和识别新的分子机制控制脂肪组织生物学通过分析新的 脂肪中HSF 1的上游调节子和下游效应子。我们的研究结果将确定新的 控制脂肪组织生物学的调节机制和与之相反的特定表观遗传特征， 肥胖脂肪，确定HSF 1是一个新的分子之间的联系，外部刺激和转录和表观遗传重建， 脂肪组织的编程，以及用于治疗代谢功能障碍的可能的新治疗靶点。 为了进行概述的研究，我们将利用独特的脂肪特异性HSF 1和腺苷受体A2 A 在我们的实验室中产生的基因敲除小鼠和多年来产生的技术和试剂， 创新的人。在目标1中，将鉴定与肥胖相关的脂肪组织中的新染色质特征， 将评估HSF 1在脂肪组织生物学和体内平衡的表观遗传控制中的作用;在目标2中， 将通过鉴定HSF 1的新分子靶点来表征脂肪细胞生物学的新调节剂 在脂肪细胞中，使用最先进的下一代测序技术，除了候选基因外， 方法;在目标3中，我们将确定调节脂肪细胞先天产热的新途径。 我们希望这些研究将阐明控制生理能量平衡的新机制。 和病理代谢状态，并将定义新的方法，以增加能量耗散和战斗 代谢性疾病