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

摘要 肥胖是一种“沉默的”流行病，也是心血管疾病发展的危险因素，包括 高血压。虽然理论上肥胖/代谢综合征是可以用现代医学、生活方式和 吃管理办法，这可不是一件小事，而我们国家与这场“无声之病”的战斗就是 不太顺利。然而，识别新的途径来减轻氧化应激和 肥胖症的炎症可以带来更好的未来治疗选择和健康管理。我们有 血红素加氧酶-1(HO-1)和细胞色素P450-环氧合酶衍生的EETs在 实施抗高血压和抗脂肪生成机制，提高胰岛素敏感性，体重 损失和能量消耗。在肥胖和糖尿病中，HO-1的表达受到抑制，脂肪组织中的EETs 都在减少。与此应用相关的是，我们发现选择性脂肪细胞HO-1的过度表达减弱 肥胖诱导的高血压，而脂肪细胞选择性缺失的HO-1缺失在缺失小鼠中显示出降低的水平 EETs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 敏感度。初步结果还表明，HO-1-EET电路的扩增激活了pGC-1α。 总之，上述观察结果支持脂肪细胞HO-1是一种 脂肪细胞产生EET和脂联素的正调节因子，导致a信号的激活 参与控制线粒体功能的Pgc1α的通路(S)，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。一个推论 其中之一是该脂肪细胞途径功能的缺陷(例如，HO-1表达受损， EET合成，和/或前列腺素C_1α水平)，似乎发生在肥胖动物模型的脂肪细胞中- 诱发性高血压和相关疾病可能是导致这种疾病的原因之一。 各州。拟议的实验旨在探索这些概念与参与 HO-1-ET-Pgc1α系统脂肪细胞缺陷在脂肪性肥胖和高血压发病机制中的作用 喂老鼠。我们将调控HO-1、CYP2C44(EETs)和Pgc1α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、氧气 消耗、体重增加、血管功能和血压以及成脂标志物和 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通路的关键信号成分包括MAP激酶和胰岛素受体磷酸化 在脂肪细胞干细胞中的表达及前列腺素C_1α对活性脂肪细胞HO-1和CYP2C44-EETs作用的依赖 在成脂过程中。本提案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调节胰岛素敏感性和高血压 着眼于确定减轻肥胖和代谢性疾病的新治疗目标。

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.