Interactions of the RAAS and a Western Diet on Insulin Metabolic Actions

RAAS 和西方饮食对胰岛素代谢作用的相互作用

• 批准号: 8442008
• 负责人: James Russell Sowers
• 金额: --
• 依托单位: HARRY S. TRUMAN MEMORIAL VA HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442008
• 关键词: Address; Affect; Aldosterone; Angiotensin II; Animals; Attenuated; Biochemical Pathway; Biological; Blood Pressure; Blood Vessels; Blood flow; C57BL/6 Mouse; Carbohydrates; Cardiac; Cardiac Myocytes; Cardiovascular system; Chronic; Clinical; Comorbidity; Consumption; Coronary; Development; Diabetes Mellitus; Diet; Dietary Fats; Dietary Sucrose; Disease; Docking; Dose; Endothelial Cells; Epidemic; Euglycemic Clamping; Exposure to; Fatty acid glycerol esters; Figs - dietary; Functional disorder; Future; Glean; Glucose; Glucose Clamp; Health; Health Care Costs; Hypertension; Image; Imaging Device; Impairment; In Vitro; Inflammation; Insulin; Insulin Resistance; Intake; Intervention; Knock-out; Liver; Mass Spectrum Analysis; Measures; Mediating; Medical; Metabolic; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardium; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Population; Positron-Emission Tomography; Prevalence; Production; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Receptor Inhibition; Receptor, Angiotensin, Type 1; Relaxation; Renin-Angiotensin-Aldosterone System; Ribosomal Protein S6 Kinase; Rodent; Rodent Model; Role; Serine; Signal Pathway; Signal Transduction; Site; Skeletal Muscle; Small Interfering RNA; Smooth Muscle Myocytes; Staging; Sucrose; Telemetry; Tissues; Tyrosine; Vascular Endothelial Cell; Vasodilation; Veterans; Western Blotting; Work; abstracting; cohort; glucose metabolism; glucose transport; glucose uptake; improved; in vivo; innovation; insulin receptor substrate 1 protein; insulin sensitivity; insulin signaling; mTOR protein; mortality; non-genomic; novel; receptor; response; sensor; skeletal

DESCRIPTION (provided by applicant): Project Summary/Abstract Impaired insulin (INS) sensitivity is a common feature of disease states such as obesity, hypertension and diabetes. A western diet (WD), especially characterized by excess intake of high fat, high sucrose and carbohydrates, is a major factor in the increased prevalence of hypertension and diabetes. These co- morbidities may be driven by a decrease in INS-mediated vasorelaxation and glucose transport in cardiovascular (CV) and skeletal muscle tissue. In addition to our WD, several other mechanisms, such as enhanced activation of the renin-angiotensin-aldosterone-system (RAAS) and associated abnormalities in INS metabolic signaling, may help explain the linkage between INS resistance and hypertension. There is emerging evidence that enhanced activation of the RAAS may promote INS resistance through the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling pathway. mTOR, a highly conserved nutrient sensor, modulates INS metabolic signaling through its phosphorylation [(p)] of S6K1, an evolutionarily conserved serine (Ser) kinase. Evidence is mounting that chronic activation of S6K1, by excessive nutrients, promotes INS resistance in fat, liver and skeletal muscle tissue through increased Ser (p) of the critical INS signaling/docking molecule, INS receptor substrate protein 1 (IRS-1), leading to impaired phosphoinositol 3 kinase (PI3-K) engagement and protein kinase B (Akt) stimulation. Our recent work indicates that S6K1 is activated by angiotensin II (Ang II) and aldosterone in CV tissue leading to diminished INS metabolic signaling and biological consequences, such as impaired nitric oxide (NO)-mediated vascular relaxation. This proposal seeks to investigate novel molecular mechanisms by which Ang II, aldosterone and a WD individually and collectively promote INS resistance in CV and skeletal muscle tissue. To evaluate the CV functional effects of INS metabolic signaling, we will utilize our state-of-the-art rodent imaging center. In the INS resistant state, myocardial and skeletal muscle glucose uptake and metabolism is impaired, leading to diastolic dysfunction, attenuated myocardial and skeletal muscle blood flow, and impaired ischemic reconditioning. We have shown that both impaired INS stimulated glucose uptake and diastolic dysfunction are related to impaired systemic and myocardial INS metabolic signaling in models of obesity and increased tissue RAAS expression. For this proposal, we will utilize novel knockout and knockdown strategies, as well as innovative rodent imaging tools, to evaluate the impact of increased S6K1 signaling (Ang II/aldosterone and/or WD) on myocardial function and coronary and skeletal microvascular blood flow responses to INS metabolic signaling. To address Objective 1, we will examine the relationship between Ang II/aldosterone/WD and S6K1 activation and INS signaling in primary cultured endothelial cells, vascular smooth muscle cells and cardiomyocytes. Metabolic signaling results will be correlated to functional measures including NO production, cardiomyocyte glucose transport and diastolic relaxation. To further explore the collective, as well as the independent, roles of Ang II/aldosterone and a WD on S6K1, Objective 2 will focus on in vivo/ex vivo effects in the S6K1-/- and C57BL/6 mice treated with Ang II/aldosterone that produces a slow pressor response and/or a WD. A cohort of animals will be treated with an AT1R blocker or a mineralocortiod receptor in doses determined by telemetry to have no effect on blood pressure in mice. INS resistance will be assessed by hyperinsulinemic and euglycemic clamp, cardiac PET scanning, ex vivo IRS-1 (p) and INS metabolic signaling, and glucose uptake in heart and skeletal muscle. Finally, in vivo INS mediated skeletal muscle arteriolar and ex vivo coronary arteriolar, NO induced relaxation, and in vivo cardiac glucose uptake and diastolic relaxation will be related to ex vivo S6K1 activity and IRS-1 site specific Se vs. tyrosine (p) and the resultant downstream IRS-1/PI3-K/Akt signaling.

描述（由申请人提供）： 项目摘要/抽象受损胰岛素（INS）敏感性是肥胖，高血压和糖尿病等疾病状态的共同特征。西方饮食（WD），尤其是以高脂肪，高蔗糖和碳水化合物摄入过多的特征，是高血压和糖尿病患病率增加的主要因素。这些共同病毒可能是由心血管（CV）和骨骼肌组织中的介导的血管瘤和葡萄糖转运的降低驱动的。除我们的WD外，其他几种机制，例如增强肾素 - 血管紧张素 - 醛固酮系统（RAAS）的激活以及INS代谢信号中相关的异常，可能有助于解释INS抗性与高血压之间的联系。 有新的证据表明，增强RAA的激活可能会通过雷帕霉素（MTOR）/S6激酶1（S6K1）信号通路促进INS抗性。 MTOR是一种高度保守的营养传感器，通过其S6K1的磷酸化[（p）]（一种进化保守的丝氨酸（SER）激酶）调节INS代谢信号传导。有证据表明，通过过量营养，S6K1的慢性激活通过临界INS信号传导/对接分子的Ser（P）促进脂肪，肝脏和骨骼肌组织的INS耐药性导致磷酸肌醇3激酶（PI3-K）参与度受损和蛋白激酶B（AKT）刺激。我们最近的工作表明，在CV组织中，S6K1被血管紧张素II（ANG II）和醛固酮激活，导致INS代谢信号传导和生物学后果减少，例如一氧化氮（NO）介导的血管降低。该提议旨在研究新的分子机制，通过这种机制，ANG II，醛固酮和WD单独并集体促进了CV和骨骼肌组织中的INS耐药性。 为了评估INS代谢信号传导的CV功能效应，我们将利用最先进的啮齿动物成像中心。在INS抗性状态下，心肌和骨骼肌葡萄糖摄取和代谢受损，导致舒张功能障碍，减弱心肌和骨骼肌血液流动以及缺血性再现。我们已经表明，在肥胖模型和组织RAAS表达增加的系统性和心肌INS代谢信号传导和组织RAAS表达增加的系统性和心肌INS代谢信号传导中，受损的INS受刺激葡萄糖摄取和舒张功能障碍均与受损的舒张功能障碍有关。对于此建议，我们将利用新颖的敲除和敲除策略以及创新的啮齿动物成像工具来评估增加S6K1信号传导（ANG II/醛固酮和/或WD）对心肌功能以及冠状动脉和骨骼微血管血流流动反应的影响启用代谢信号。 为了解决目标1，我们将研究ANG II/醛固酮/WD与S6K1激活与INS信号转导之间的关系，血管平滑肌细胞和心肌细胞中的INS信号传导。 代谢信号结果将与功能措施相关，包括无生产，心肌细胞葡萄糖转运和舒张期松弛。 为了进一步探索ANG II/醛固酮和WD在S6K1上的集体以及独立的角色，目标2将重点关注S6K1 - / - 和C57BL/6小鼠的体内/Ex Vivo效应。 /醛固酮产生缓慢的压力响应和/或WD。通过遥测确定的剂量，将用AT1R阻滞剂或矿体皮层受体处理一组动物，对小鼠血压没有影响。 INS耐药性将通过高胰岛素和葡萄糖夹，心脏PET扫描，Ex Vivo IRS-1（P）和INS代谢信号传导以及心脏和骨骼肌中的葡萄糖吸收来评估。最后，体内介导的骨骼肌小动脉和外体冠状动脉小动脉，没有诱导的放松，并且体内心脏葡萄糖摄取和舒张期放松将与EX VIVO S6K1活性以及IRS-1站点特异性SE与特定的SE与酪氨酸（P）和酪氨酸（P）和酪氨酸（P）和酪氨酸（P）和酪氨酸（P）和酪氨酸（P）和最终的下游IRS-1/PI3-K/AKT信号传导。