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.

肥胖症与延伸超出心血管疾病（CVD）的广泛相关 常见的合并症，例如血脂异常和糖尿病，CVD风险增加证明 “代谢健康的肥胖”个体。但是，对推动这一点的机制有充分的理解 协会仍然是未满足的需求。脂肪组织在内分泌器官中起着广泛的作用 根据代谢状态，脂肪沉积，证明对心脏生理有多种影响 位置（例如内脏与皮下）和主要细胞类型（例如棕色与白色）。因此，长期 我实验室的目标是提高我们对脂肪组织衍生的内分泌的机械理解 向心肌发出信号，特别是如何受到（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，我们最近将RNA结合蛋白HUR确定为脂肪的新介体 心脏信号轴并显示了肥胖的皮下WAT（SCWAT）的HUR表达 小鼠和人类对应于改善的心脏功能。具体来说，我们最近表明 小鼠HUR的脂肪细胞特异性缺失（adipo-hur - / - ）导致蝙蝠介导的热源性不足 代谢，与心血管健康密切相关，足以诱导心脏 肥大和纤维化。初步数据表明，这种心脏病理是由Hur依赖的 脂肪衍生的细胞外蔬菜（AD-EV）。 我们的中心假设是，脂肪组织中的HUR表达降低有助于心脏 通过破坏自适应热发生和AD-EV介导的内分泌信号传导的病理学。 AIM 1将阐明HUR介导BAT中钙循环的机制和功能 这些依赖性途径对热代谢的贡献。工作的假设是 HUR通过调节钙（CA2+）循环来介导BAT中的热发生。 AIM 2将描绘 HUR依赖性AD-EV在心脏肥大中的功能作用，并确定 人脂肪组织和心脏功能中的HUR活性和基因表达。工作假设是 通过遗传缺失或肥胖，脂肪组织中HUR表达的丧失介导 肥厚的内分泌信号通过AD-EV向心肌发出。 考虑到我们最近的出版物，蝙蝠活动与 人类的心血管健康，以及Scherer及其同事的发现，表明大型循环电动汽车 从脂肪细胞直接撞击体内心肌菌。我们的结果将提高我们的机制 通过CA2+循环（2）对（1）HUR作为热生成的介体，（2）脂肪组织信号传导 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。