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

肥胖与心血管疾病（CVD）的增加广泛相关， 常见的合并症，如血脂异常和糖尿病，如CVD风险增加所证明， “代谢健康的肥胖者”然而，对驱动这一机制的充分理解 但这仍然是一个未得到满足的需求。脂肪组织作为内分泌器官起着广泛的作用， 显示对心脏生理学有多种影响，取决于代谢状态、脂肪储存 位置（例如内脏与皮下）和原代细胞类型（例如棕色与白色）。因此，长期 我的实验室的目标是增加我们对脂肪组织来源的内分泌的机制的理解， 信号传导到心肌，特别是它如何受到（1）棕色脂肪组织（BAT）介导的 能量消耗和（2）脂肪组织稳态的变化。 为此，我们最近鉴定了RNA结合蛋白HuR作为脂肪代谢的新介质。 心脏信号传导轴，并已显示减少HuR表达的皮下WAT（scWAT）从肥胖 小鼠和人的心脏功能下降。具体来说，我们最近表明， 小鼠脂肪细胞特异性HuR缺失（Adipo-HuR-/-）导致BAT介导的产热因子缺乏 代谢，这与心血管健康密切相关，并足以诱导心脏 肥大和纤维化。初步数据表明，这种心脏病理学是由HuR依赖性 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， 目的1将阐明HuR介导BAT中钙循环的机制，以及HuR在BAT中的功能作用。 这些HuR依赖性途径对产热代谢的贡献。工作假设是， HuR通过调节钙（Ca 2+）循环介导BAT中的产热。目标2将描述 HuR依赖性Ad-EV在心肌肥厚中的功能作用，并确定HuR依赖性Ad-EV与心肌肥厚之间的翻译联系。 人脂肪组织中HuR活性和基因表达与心脏功能。工作假设是 脂肪组织中HuR表达的缺失，无论是通过基因缺失还是肥胖，都介导了一个促生长因子， 通过Ad-EV将肥大内分泌信号传导至心肌。 鉴于我们最近的出版物，这项工作是及时和创新的， 谢勒及其同事的研究结果表明， 直接影响体内的心肌细胞。我们的研究结果将增加我们的机械 理解（1）HuR作为通过Ca 2+循环的产热介质，（2）脂肪组织向 心肌;（3）脂肪组织基因表达与心脏功能之间的翻译联系。

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.