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: 8971983
• 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/8971983
• 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; Dietary Fats; Dietary Sucrose; Disease; Docking; Dose; Endothelial Cells; Epidemic; Euglycemic Clamping; Exposure to; FRAP1 gene; 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; Muscle; Myocardial; Myocardium; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Outcome; Pathway interactions; 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 Smooth Muscle; 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; knock-down; mortality; non-genomic; novel; novel therapeutics; receptor; response; sensor; skeletal; western diet

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/摘要 胰岛素 (INS) 敏感性受损是肥胖、高血压和糖尿病等疾病的一个共同特征。西方饮食（WD），特别是以过量摄入高脂肪、高蔗糖和碳水化合物为特征，是高血压和糖尿病患病率增加的主要因素。这些合并症可能是由于心血管 (CV) 和骨骼肌组织中 INS 介导的血管舒张和葡萄糖转运减少所致。除了我们的 WD 之外，其他几种机制，例如肾素-血管紧张素-醛固酮系统 (RAAS) 的增强激活以及 INS 代谢信号的相关异常，可能有助于解释 INS 抵抗和高血压之间的联系。 新的证据表明，RAAS 激活的增强可能通过哺乳动物雷帕霉素靶点 (mTOR)/S6 激酶 1 (S6K1) 信号通路促进 INS 耐药。 mTOR 是一种高度保守的营养传感器，通过 S6K1（一种进化上保守的丝氨酸 (Ser) 激酶）的磷酸化 [(p)] 来调节 INS 代谢信号。越来越多的证据表明，过量营养导致 S6K1 慢性激活，通过增加关键 INS 信号/对接分子、INS 受体底物蛋白 1 (IRS-1) 的 Ser (p)，促进脂肪、肝脏和骨骼肌组织中的 INS 抵抗。导致磷酸肌醇 3 激酶 (PI3-K) 参与和蛋白激酶 B (Akt) 刺激受损。我们最近的工作表明，S6K1 被 CV 组织中的血管紧张素 II (Ang II) 和醛固酮激活，导致 INS 代谢信号减弱和生物学后果，例如一氧化氮 (NO) 介导的血管舒张受损。该提案旨在研究 Ang II、醛固酮和 WD 单独和共同促进 CV 和骨骼肌组织中 INS 抵抗的新分子机制。 为了评估 INS 代谢信号对 CV 功能的影响，我们将利用我们最先进的啮齿动物成像中心。在INS抵抗状态下，心肌和骨骼肌葡萄糖摄取和代谢受损，导致舒张功能障碍、心肌和骨骼肌血流减弱以及缺血再适应受损。我们已经证明，INS 刺激的葡萄糖摄取受损和舒张功能障碍都与肥胖模型中全身和心肌 INS 代谢信号受损以及组织 RAAS 表达增加有关。对于本提案，我们将利用新颖的敲除和敲低策略以及创新的啮齿动物成像工具来评估 S6K1 信号传导（Ang II/醛固酮和/或 WD）增加对心肌功能以及冠状动脉和骨骼微血管血流反应的影响INS 代谢信号。 为了实现目标 1，我们将检查原代培养的内皮细胞、血管平滑肌细胞和心肌细胞中 Ang II/醛固酮/WD 与 S6K1 激活和 INS 信号传导之间的关系。 代谢信号结果将与功能测量相关，包括一氧化氮生成、心肌细胞葡萄糖转运和舒张舒张。 为了进一步探索 Ang II/醛固酮和 WD 对 S6K1 的集体以及独立作用，目标 2 将重点关注用 Ang II 治疗的 S6K1-/- 和 C57BL/6 小鼠的体内/离体效应/醛固酮产生缓慢的升压反应和/或WD。一组动物将接受 AT1R 阻滞剂或盐皮质激素受体的治疗，剂量通过遥测确定，对小鼠的血压没有影响。 INS 抵抗将通过高胰岛素和正常血糖钳夹、心脏 PET 扫描、离体 IRS-1 (p) 和 INS 代谢信号以及心脏和骨骼肌中的葡萄糖摄取来评估。最后，体内 INS 介导的骨骼肌小动脉和离体冠状动脉、NO 诱导的舒张以及体内心脏葡萄糖摄取和舒张舒张将与离体 S6K1 活性和 IRS-1 位点特异性 Se 与酪氨酸 (p) 和由此产生的下游 IRS-1/PI3-K/Akt 信号传导。