Post-transcriptional control of adipose tissue gene expression as an endocrine mediator of cardiac pathology

脂肪组织基因表达的转录后控制作为心脏病病理学的内分泌介质

• 批准号: 10675102
• 负责人: Michael Tranter
• 金额: $ 62.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675102
• 关键词: Adipocytes; Adipose tissue; Adrenergic Agents; Affect; American; Antigens; Binding; Brown Fat; Calcium; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Chronic; Clinical; Cytoplasm; Data; Development; Diabetes Mellitus; Disease; Dyslipidemias; Endocrine; Endocrine Glands; Endoplasmic Reticulum; Energy Metabolism; Gene Expression; Generations; Genes; Genetic; Goals; Heart Hypertrophy; Homeostasis; HuR protein; Human; Laboratories; Link; Lipids; Location; Mediating; Mediator; Messenger RNA; Metabolic; Metabolism; Mus; Muscle Cells; Myocardial; Myocardium; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathology; Pathway interactions; Physiology; Post-Transcriptional Regulation; Proteins; Publications; Publishing; RNA; RNA-Binding Proteins; Rattus; Regulation; Role; RyR2; Signal Transduction; Stroke; Thermogenesis; Tissue Sample; Ventricular; Visceral; Work; cardiovascular disorder risk; cardiovascular health; cell type; comorbidity; coronary fibrosis; extracellular vesicles; heart function; in vivo; inducible Cre; innovation; knock-down; mouse model; novel; obese person; overexpression; pharmacologic; subcutaneous; vesicle transport

Obesity has been widely associated with increased cardiovascular disease (CVD) extending beyond common co-morbidities, such as dyslipidemia and diabetes, as evidenced by increased CVD risk in ‘metabolically healthy obese’ individuals. However, a full understanding of the mechanisms that drive this association remains an unmet need. Adipose tissue serves a broad role as an endocrine organ and has been shown to have a multitude of effects on cardiac physiology depending on metabolic state, adipose depot location (e.g visceral vs. subcutaneous), and primary cell type (e.g. brown vs. white). As such, the long-term goals of my laboratory are to increase our mechanistic understanding of adipose tissue-derived endocrine signaling to the myocardium and specifically how it is impacted by (1) brown adipose tissue (BAT)-mediated energy expenditure and (2) changes in adipose tissue homeostasis. To this end, we have recently identified the RNA binding protein HuR as a novel mediator of the adipose- cardiac signaling axis and have shown decreased HuR expression in subcutaneous WAT (scWAT) from obese mice and humans corresponds with decreased cardiac function. Specifically, we recently showed that adipocyte-specific deletion of HuR in mice (Adipo-HuR-/-) leads to a deficiency of BAT-mediated thermogenic metabolism, which is strongly associated with cardiovascular health, and is sufficient to induce cardiac hypertrophy and fibrosis. Preliminary data suggests that this cardiac pathology is driven by HuR-dependent adipose-derived extracellular vesicles (Ad-EVs). Our central hypothesis is that decreased HuR expression in adipose tissue contributes to cardiac pathology through disruption of adaptive thermogenesis and Ad-EV mediated endocrine signaling. Aim 1 will elucidate the mechanisms by which HuR mediates calcium cycling in BAT and the functional contribution of these HuR-dependent pathways to thermogenic metabolism. The working hypothesis is that HuR mediates thermogenesis in BAT through regulation of calcium (Ca2+) cycling. Aim 2 will delineate the functional role of HuR-dependent Ad-EVs on cardiac hypertrophy and identify the translational link between HuR activity and gene expression in human adipose tissue and cardiac function. The working hypothesis is that the loss of HuR expression in adipose tissue, either through genetic deletion or obesity, mediates a pro- hypertrophic endocrine signaling to the myocardium via Ad-EVs. This work is timely and innovative given our recent publications, the association of BAT activity with cardiovascular health in humans, and findings from Scherer and colleagues showing that large circulating EVs from adipocytes directly impact cardiomycotyes in vivo. Our results will increase our mechanistic understanding of (1) HuR as a mediator of thermogenesis via Ca2+ cycling, (2) adipose tissue signaling to the myocardium, and (3) the translational link between adipose tissue gene expression and cardiac function.

肥胖与心血管疾病（CVD）的增加广泛相关，其范围超出了 常见的合并症，如血脂异常和糖尿病，心血管疾病风险增加就证明了这一点 然而，“代谢健康的肥胖”个体需要充分了解其驱动机制。 脂肪组织作为内分泌器官发挥着广泛的作用，并且一直是一个未满足的需求。 显示对心脏生理有多种影响，具体取决于代谢状态、脂肪库 位置（例如内脏与皮下）和原代细胞类型（例如棕色与白色）。 我实验室的目标是增加我们对脂肪组织源性内分泌的机制理解 向心肌发出信号，特别是它如何受到 (1) 棕色脂肪组织 (BAT) 介导的影响 能量消耗和（2）脂肪组织稳态的变化。 为此，我们最近发现 RNA 结合蛋白 HuR 作为脂肪- 心脏信号轴并显示肥胖者皮下 WAT (scWAT) 中 HuR 表达降低 具体来说，我们最近表明，小鼠和人类的心脏功能下降。 小鼠脂肪细胞特异性 HuR 缺失 (Adipo-HuR-/-) 导致 BAT 介导的生热缺陷 新陈代谢，与心血管健康密切相关，足以诱发心脏 初步数据表明，这种心脏病是由 HuR 依赖性驱动的。 脂肪来源的细胞外囊泡（Ad-EV）。 我们的中心假设是脂肪组织中 HuR 表达的减少有助于心脏 通过破坏适应性产热和 Ad-EV 介导的内分泌信号传导来调节病理学。 目标 1 将阐明 HuR 介导 BAT 中钙循环的机制以及功能 这些 HuR 依赖性途径对生热代谢的贡献是这样的。 HuR 通过调节钙 (Ca2+) 循环来介导 BAT 中的生热作用。目标 2 将描述 HuR 依赖性 Ad-EV 对心脏肥大的功能作用，并确定之间的翻译联系 人类脂肪组织中的 HuR 活性和基因表达以及心脏功能。 脂肪组织中 HuR 表达的丧失，无论是通过基因缺失还是肥胖，都会介导一种亲 通过 Ad-EVs 向心肌发送肥厚内分泌信号。 鉴于我们最近的出版物、BAT 活动与 人类心血管健康，Scherer 及其同事的研究结果表明，大量循环的 EV 来自脂肪细胞的直接影响体内心肌细胞我们的结果将增加我们的机制。 了解 (1) HuR 作为通过 Ca2+ 循环产生热量的介质，(2) 脂肪组织向 心肌，以及（3）脂肪组织基因表达与心脏功能之间的翻译联系。