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

肥胖已被广泛地与心血管疾病(CVD)的增加联系在一起 常见的并存疾病，如血脂异常和糖尿病，心血管疾病风险增加就是明证。 “新陈代谢健康的肥胖人群”。然而，对驱动这一现象的机制有充分的了解 联想仍然是一个未得到满足的需求。脂肪组织作为内分泌器官具有广泛的作用，一直以来 显示出对心脏生理的多种影响取决于新陈代谢状态，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)。因此，从长远来看， 我的实验室的目标是增加我们对脂肪组织衍生内分泌的机械理解 (1)棕色脂肪组织(BAT)介导的对心肌的信号传导，特别是它是如何受到影响的 能量消耗和(2)脂肪组织动态平衡的变化。 为此，我们最近发现RNA结合蛋白HUR是一种新的脂肪- 心脏信号轴，并显示肥胖患者皮下水(ScWAT)中Hur的表达降低 老鼠和人类的心脏功能都会下降。具体地说，我们最近展示了 小鼠脂肪细胞特异性HUR基因缺失(Adipo-Hur-/-)导致BAT介导的生热作用缺失 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，这种心脏病理是由HUR依赖性驱动的 脂肪来源的细胞外小泡(Ad-EVS)。 我们的中心假设是，脂肪组织中HUR表达的减少有助于心脏 通过干扰适应性产热和Ad-EV介导的内分泌信号而导致的病理学改变。 目的1阐明HUR介导蝙蝠钙循环的机制和功能 这些依赖于HUR的途径对生热代谢的贡献。工作假说是 HUR通过调节钙循环来调节蝙蝠产热。目标2将描述 Hur依赖的Ad-EVS在心肌肥厚中的功能作用及其翻译联系 人脂肪组织中HUR活性和基因表达与心功能工作假说是 脂肪组织中HUR表达的丧失，无论是由于基因缺失还是肥胖，都介导了一种有利于 通过Ad-EVS向心肌发出肥大的内分泌信号。 这项工作是及时和创新的，考虑到我们最近的出版物，蝙蝠活动与 人类的心血管健康，谢勒和他的同事的发现表明，循环中的大型电动汽车 来自脂肪细胞的物质直接影响体内的心肌细胞。我们的结果将增加我们的机械性 了解(1)HUR通过钙循环作为产热的中介，(2)脂肪组织向 (3)脂肪组织基因表达与心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.