Adipocyte EET-PGC1alpha-HO-1 in Obesity-driven Hypertension

肥胖引起的高血压中的脂肪细胞 EET-PGC1α-HO-1

• 批准号: 9769285
• 负责人: Nader G. Abraham
• 金额: $ 50.29万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769285
• 关键词: Acids; Adipocytes; Adverse effects; Animal Model; Animals; Antihypertensive Agents; Antioxidants; Attenuated; Biogenesis; Blood Pressure; Blood Vessels; Body Weight decreased; Bone Marrow; Cardiovascular Diseases; Cardiovascular system; Cytochrome P450; Data; Development; Diabetes Mellitus; Diet; Disease; Eating; Energy Metabolism; Epidemic; Exhibits; Eye; Fatty acid glycerol esters; Funding; Future; Gene Expression; Genes; Goals; Health; High Fat Diet; Hyperglycemia; Hypertension; Impairment; Inflammation; Inflammatory; Insulin Receptor; Insulin Resistance; Knockout Mice; Knowledge; Lead; Life Style; Mediating; Medical; Metabolic; Metabolic Diseases; Metabolic syndrome; Methods; Mitochondria; Mitogen-Activated Protein Kinases; Modernization; Mus; Names; Obesity; Oxidative Stress; Oxygen Consumption; Pathogenesis; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phenotype; Phosphorylation; Production; Regulatory Pathway; Risk Factors; Rodent; Signal Pathway; Signal Transduction; Signaling Molecule; Solid; Stem cells; Stroke; System; Testing; Tissues; Vascular Diseases; Vasodilator Agents; Weight Gain; Work; adipocyte differentiation; adiponectin; attenuation; cytokine; design; experimental study; feeding; glucose uptake; health management; heme oxygenase-1; indexing; inflammatory marker; insulin sensitivity; lipid biosynthesis; metabolic phenotype; new therapeutic target; novel; novel therapeutics; obesity development; overexpression; prevent; response; transcription factor

SUMMARY Obesity is a “silent” epidemic disease and a risk factor for development of cardiovascular disease including hypertension. Although obesity/metabolic syndrome is theoretically treatable with modern medical, lifestyle and eating management methods, this is not a trivial undertaking and our national battle with this “silent disease” is not going well. However, identifying novel pathways that mitigate the deleterious effects of oxidative stress and inflammation in obesity can lead to better future treatment options and health management. We have successfully implicated heme oxygenase-1 (HO-1) and cytochrome P450-epoxygenase-derived EETs in the implementation of anti-hypertensive and anti-adipogenic mechanisms that enhances insulin sensitivity, weight loss and energy expenditure. In obesity and diabetes, HO-1 expression is repressed and EETs in fat tissues are decreased. Relevant to this application we found that selective adipocyte HO-1 overexpression attenuated obesity-induced hypertension, while adipocyte-selective HO-1 deletion in null mice exhibit diminished levels of EETs and PGC1α, a transcription factor known to regulate mitochondrial biogenesis and peripheral insulin sensitivity. Preliminary results also revealed that amplification of the HO-1-EET circuit activates PGC-1α. Collectively, the aforementioned observations support the hypothesis that HO-1 of adipocytes is a positive regulator of adipocyte EET production and adiponectin, leading to activation of a signaling pathway involving PGC1α which controls mitochondrial function(s), decreases formation of ROS, and increases insulin sensitivity, all of which may contribute to set the levels of blood pressure. A corollary of this is that a deficit in the functionality of this adipocyte pathway (e.g., impaired HO-1 expression, EET synthesis, and/or PGC1α level), as appears to occur in adipocytes of animal models of obesity- induced hypertension and related conditions may be a contributor to the pathogenesis of such disease states. The proposed experimentation is designed to explore these concepts in relation to the involvement of a deficit in adipocytes of the HO-1-EET-PGC1α system in the pathogenesis of obesity and hypertension in fat fed mice. We will manipulate the expression of HO-1, CYP2C44(EETs) and PGC1α genes within adipocytes and assess the effect on metabolic and cardiovascular parameters including insulin sensitivity, oxygen consumption, weight gain, vascular function and blood pressure as well as on adipogenic markers and signaling molecules that are indices of adipocyte phenotype in health and disease. We will further focus on the key signaling components of the PGC1α pathway including MAP kinases, and insulin receptor phosphorylation in adipocyte stem cells and the reliance of PGC1α actions on active adipocyte HO-1 and CYP2C44-EETs during adipogenesis. The experiments outlined in this proposal will provide us with a solid working knowledge of how HO-1-EET interact with key signaling pathways to regulate insulin sensitivity and hypertension with an eye on the identification of new therapeutic targets for attenuation of obesity and metabolic disease.

概括 肥胖是一种“无声”的流行病，也是心血管疾病发展的危险因素，包括 高血压。尽管肥胖/代谢综合征理论上可以通过现代医学、生活方式和生活方式来治疗 饮食管理方法，这不是一件小事，我们全国与这种“沉默的疾病”的战斗 进展不顺利。然而，确定减轻氧化应激有害影响的新途径 肥胖引起的炎症可以带来更好的未来治疗选择和健康管理。我们有 成功地将血红素加氧酶-1 (HO-1) 和细胞色素 P450 环氧合酶衍生的 EET 与 实施抗高血压和抗脂肪形成机制，增强胰岛素敏感性、体重 损失和能量消耗。在肥胖和糖尿病中，脂肪组织中的 HO-1 表达和 EET 受到抑制 减少。与此应用相关，我们发现选择性脂肪细胞 HO-1 过表达减弱 肥胖诱发的高血压，而无效小鼠中脂肪细胞选择性 HO-1 缺失则表现出脂肪细胞水平降低 EET 和 PGC1α（一种已知调节线粒体生物发生和外周胰岛素的转录因子） 敏感性。初步结果还表明，HO-1-EET 电路的放大会激活 PGC-1α。 总的来说，上述观察结果支持脂肪细胞的 HO-1 是一种脂肪细胞的假设。 脂肪细胞 EET 产生和脂联素的正调节因子，导致信号传导的激活 涉及 PGC1α 的通路控制线粒体功能，减少 ROS 的形成，以及 增加胰岛素敏感性，所有这些都可能有助于设定血压水平。推论 其中之一是该脂肪细胞途径的功能缺陷（例如，HO-1 表达受损， EET 合成和/或 PGC1α 水平），似乎发生在肥胖动物模型的脂肪细胞中 - 诱发的高血压和相关病症可能是此类疾病的发病机制的一个因素 州。拟议的实验旨在探索与参与相关的这些概念 脂肪细胞 HO-1-EET-PGC1α 系统缺陷在肥胖和高血压发病机制中的作用 喂老鼠。我们将操纵脂肪细胞内 HO-1、CYP2C44(EETs) 和 PGC1α 基因的表达 并评估对代谢和心血管参数的影响，包括胰岛素敏感性、氧气 消耗、体重增加、血管功能和血压以及脂肪生成标记物和 信号分子是健康和疾病中脂肪细胞表型的指标。我们将进一步关注 PGC1α 通路的关键信号传导成分，包括 MAP 激酶和胰岛素受体磷酸化 脂肪细胞干细胞中的 PGC1α 作用对活性脂肪细胞 HO-1 和 CYP2C44-EET 的依赖 在脂肪生成过程中。本提案中概述的实验将为我们提供扎实的工作知识 HO-1-EET 如何与关键信号通路相互作用以调节胰岛素敏感性和高血压 着眼于确定减轻肥胖和代谢疾病的新治疗靶点。

项目成果

Sirt6 Deacetylase: A Potential Key Regulator in the Prevention of Obesity, Diabetes and Neurodegenerative Disease.

• DOI: 10.3389/fphar.2020.598326
• 发表时间: 2020
• 期刊: Frontiers in pharmacology
• 影响因子: 5.6
• 作者: Raj S;Dsouza LA;Singh SP;Kanwal A
• 通讯作者: Kanwal A

The Peroxisome Proliferator-Activated Receptor-Gamma Coactivator-1α-Heme Oxygenase 1 Axis, a Powerful Antioxidative Pathway with Potential to Attenuate Diabetic Cardiomyopathy.

过氧化物酶体增殖物激活受体-γ 辅激活剂-1α-血红素加氧酶 1 轴，一种强大的抗氧化途径，具有减轻糖尿病心肌病的潜力。

• DOI: 10.1089/ars.2019.7989
• 发表时间: 2020
• 期刊: Antioxidants & redox signaling
• 影响因子: 6.6
• 作者: Waldman,Maayan;Arad,Michael;Abraham,NaderG;Hochhauser,Edith
• 通讯作者: Hochhauser,Edith