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.

总结 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， 高血压虽然肥胖/代谢综合征理论上可以用现代医学、生活方式和方法治疗， 吃管理方法，这不是一个微不足道的事业，我们的国家与这种“沉默的疾病”的斗争是 不太顺利然而，鉴定减轻氧化应激的有害影响的新途径， 肥胖症中的炎症可以导致更好的未来治疗选择和健康管理。我们有 成功地暗示血红素加氧酶-1（HO-1）和细胞色素P450-环氧合酶衍生的Ehrs在 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，HO-1表达受到抑制，脂肪组织中出现EET 减少了。与该应用相关，我们发现选择性脂肪细胞HO-1过表达减弱了 肥胖诱导的高血压，而脂肪细胞选择性HO-1缺失在裸小鼠中表现出降低的水平， 已知调节线粒体生物合成和外周胰岛素的转录因子E2和PGC 1 α 灵敏度初步结果还表明，HO-1-EET回路的放大激活PGC-1α。 总的来说，上述观察结果支持脂肪细胞的HO-1是一种细胞因子的假设。 脂肪细胞EET生产和脂联素的正调节剂，导致信号转导的激活 涉及PGC 1 α的途径，其控制线粒体功能，减少ROS的形成， 增加胰岛素敏感性，所有这些都可能有助于设定血压水平。一个推论 其中之一是这种脂肪细胞途径的功能性缺陷（例如，HO-1表达受损， EET合成和/或PGC 1 α水平），如肥胖动物模型的脂肪细胞中出现的那样- 诱发性高血压和相关疾病可能是这种疾病发病机制的一个因素 states.拟议的实验旨在探讨这些概念的参与， 脂肪细胞HO-1-EET-PGC 1 α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HO-1、CYP 2C 44（Ehrs）和PGC 1 α基因在脂肪细胞中的表达 并评估对代谢和心血管参数的影响，包括胰岛素敏感性、氧 消耗，体重增加，血管功能和血压以及脂肪形成标志物， 这些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 PGC 1 α通路的关键信号传导组分，包括MAP激酶和胰岛素受体磷酸化 在脂肪干细胞中的作用以及PGC 1 α对活性脂肪细胞HO-1和CYP 2C 44-E2的依赖性 在脂肪形成过程中。在这个建议中概述的实验将为我们提供坚实的工作知识 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