Does the Epigenome Hold Clues to Leptin-associated Hypertension in Obesity?
Does the Epigenome Hold Clues to Leptin-associated Hypertension in Obesity?
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DOI：
10.1165/rcmb.2021-0199ed
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发表时间：
2021-08
影响因子：
6.4
通讯作者：
Lingappan K
中科院分区：
文献类型：
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作者：
Lingappan K
肥胖是一种由许多因素引起的疾病，包括遗传因素、环境因素和行为因素，以及在发达国家和发展中国家不断扩大的健康问题。肥胖也是大多数原发性高血压的原因，瘦素和交感神经系统在肥胖相关高血压中的作用特别耐人寻味。瘦素是一种神经内分泌激素(ob基因产物)，主要由脂肪组织分泌，是新陈代谢和脂肪积累的重要调节因子。具有ob基因突变的动物肥胖，并在注射瘦素后体重减轻(3)。肥胖患者的瘦素水平会升高，并与体内脂肪质量的百分比成正比(4)。瘦素主要作用于大脑，但瘦素在外周组织中的作用越来越受到重视。瘦素通过充当大脑的传入信号来调节身体的能量储存，从而调节代谢反应。此外，itmayalsoaffectbloodpressureandcontributetothe通过在循环系统或肾脏水平激活交感神经，在肥胖中发生高血压(1)。瘦素通过其受体激活下游信号通路。由于选择性剪接产生了多种瘦素受体亚型，其中长亚型(LepRb)是研究最深入的(5)。LepRb属于IL-6受体家族的细胞因子受体，通过JAK2(6)发出信号。有趣的是，在肥胖患者中，循环中高水平的瘦素可能不会产生有益的中枢代谢反应，从而导致体重减轻，相反，可能会对动脉血压和肾交感神经活动产生有害影响。这种现象被称为选择性瘦素抵抗，导致肥胖相关的高血压(7，8)。因此，确定瘦素导致肥胖相关高血压的机制非常重要，以帮助指导这类患者的最佳治疗。在本期《华尔街日报》上，Yeung及其同事(第214-221页)在他们先前工作的基础上描绘了瘦素调节颈动脉小体(CB)球体细胞Trpm7(瞬时受体电位Melastatin 7)表达的分子机制(9)。该项目的中心假设是瘦素对Trpm7进行表观遗传调控。CB是一种化学感受器，位于颈动脉分叉处，在低氧反应中起重要作用。CB内的球状细胞是检测缺氧、高碳酸血症或酸中毒的化学感受器。然后，这些细胞通过颈动脉窦神经传递到中央延髓中心，激活交感神经系统(10)。本研究使用稳定表达LEPRb的未分化大鼠嗜铬细胞瘤(PC12)细胞作为CB的体外模型系统
Obesity is a disease caused by many factors, including genetic, environmental, andbehavioral, andisanexpandinghealthcrisisbothin developed and developing countries. Obesity also accounts for most essential hypertension cases, and the role of leptin and the sympathetic nervous system in obesity-associated hypertension is particularly intriguing (1). Leptin is a neuroendocrine hormone (product of the ob gene) secreted mainly by adipose tissue and functions as an essential regulator of metabolism and fat accumulation (2). Animals with mutations in the ob gene are obese and lose weight upon leptin administration (3). Leptin levels are increased in patients who are obese and are directly proportional to the percentage of fat mass in the body (4). Leptin acts primarily on the brain, but the role of leptin in peripheral tissuesisincreasinglyappreciated. Leptinmediatesametabolicresponse by acting as an afferent signal to the brain to regulate the bodyes energy stores. Inaddition, itmayalsoaffectbloodpressureandcontributetothe occurrence of hypertension in obesity through sympathetic activation in the circulatory system or at the renal level (1). Leptin acts through its receptor to activate the downstream signaling pathways. There are multiple leptin receptor isoforms produced because of alternative splicing, of which the long isoform (LepRb) is the most well studied (5). LepRb belongs to the IL-6 receptor family of cytokine receptors, which signal via JAK2 (6).Interestingly, in patients who are obese, the high circulating leptin levels may not have the beneficial central metabolic responses that mediate weight loss but may instead have harmful effects on arterial pressure and renal sympathetic nerve activity. This phenomenon, termed selective leptin resistance, contributes to obesity-associated hypertension (7, 8). Accordingly, itisvitaltoidentifythemechanismsby which leptin contributes to obesity-associated hypertension to help guide optimal therapies in this patient population. In this issue of the Journal, Yeung and colleagues (pp. 214-221) build on their previous work to delineate the molecular mechanisms by which leptin regulatesTrpm7 (transient receptor potential melastatin 7) expression in the carotid body (CB) glomus cells (9). The central hypothesis of this project was that leptin epigenetically regulatesTrpm7. The CB functions as a chemosensory organ and is located at the bifurcation of the carotid artery, where it plays a significant role in the response to hypoxia. The glomus cells within the CB are the chemoreceptors that detect hypoxia, hypercapnia, or acidosis. These cells then transmit to the central medullary centers through the carotid sinus nerve to activate the sympathetic nervous system (10). This study used the undifferentiated rat pheochromocytoma (PC12) cells stably expressing LEPRb (PC12LEPRb) as an in vitro model system for the CB