Metabolic Determinants of Cardiovascular Dysfunction in Obesity

描述（由申请人提供）：心血管疾病继发的发病率和死亡率是肥胖患者的主要健康问题。肥胖患者背负着一系列与超重相关的代谢功能障碍。其中最显著的是胰岛素抵抗，它会导致血浆化学的有害变化，代偿性胰岛素过量产生，最终导致胰腺2细胞衰竭和2型糖尿病。由于肥胖患者同时存在代谢和心血管功能障碍，人们普遍怀疑这两者是因变量。这在多大程度上是正确的，以及将代谢和心血管疾病联系起来的机制是未知的。在这项应用的初步数据中，我们建立了一种新的小鼠模型，其中从肥胖小鼠中删除了胰岛素受体脱敏基因蛋白酪氨酸磷酸酶1B （PTP1B）。结果是小鼠持续肥胖并纠正了外周胰岛素抵抗。肥胖小鼠在体外表现出一氧化氮介导的微血管内皮血管舒张功能受损，这一缺陷通过PTP1B缺失得到纠正。这表明胰岛素抵抗是肥胖引起的代谢功能障碍的原因。这些微血管缺陷的分子机制将在Aim 1中确定。在Aim 2中，将以血流、血压和血管重塑为终点，确定纠正肥胖小鼠胰岛素抵抗对心血管的影响。虽然初步数据提供了新的证据，表明胰岛素抵抗和心血管功能障碍有关，但这种关系的性质尚不清楚。肥胖小鼠的高水平HbA1c表明环境有利于非酶糖基化，这种关联通过晚期糖基化终产物受体（RAGE）的表达增加而加强。这两种缺陷在肥胖PTP1B缺失小鼠中得到纠正，胰岛素抵抗得到改善。这导致我们假设RAGE是胰岛素抵抗和心血管功能障碍之间的机制联系，这一假设将在Aim 3中通过产生新的双KO小鼠（缺乏RAGE的肥胖小鼠）来验证。综上所述，这些研究将为肥胖诱导的代谢功能障碍的机制、介质和生理影响提供新的信息。成功完成这些目标可能会确定新的目标，以帮助治疗最常见的肥胖临床结果。公共卫生相关性：心血管疾病是肥胖人群最大的健康威胁，部分原因是伴随肥胖的代谢功能障碍。申请中提出的研究确定了两个新的治疗靶点PTP1B和RAGE，它们可能通过打破“代谢联系”来解开肥胖与心血管疾病之间的有害关系。这些实验的完成不仅将潜在地验证这些新的目标，而且还将更好地阐明为什么肥胖会导致心血管疾病。

DESCRIPTION (provided by applicant): Morbidity and mortality secondary to cardiovascular disease is the major health problem in obese patients. Obese patients are burdened with an array of metabolic dysfunctions associated with excess weight. Most notable of these is insulin resistance which causes deleterious changes in plasma chemistry, compensatory over-production of insulin and eventual failure of the pancreatic 2-cell and Type 2 diabetes. Because obese patients present with both metabolic and cardiovascular dysfunction, it is widely suspected that the two are dependent variables. The extent to which this is true and the mechanisms linking metabolic and cardiovascular disease are unknown. In preliminary data for this application, we have generated a novel mouse model in which an insulin receptor desensitizing gene, protein tyrosine phosphatase 1B (PTP1B) is deleted from obese mice. The result is a mouse with persistent obesity and correction of peripheral insulin resistance. Obese mice show impairment of microvascular endothelial NO-mediated vasodilation in vitro, a defect corrected by PTP1B deletion. This suggests that insulin resistance is the causal aspect of obesity-induced metabolic dysfunction. The molecular mechanisms underlying these microvascular defects will be determined in Aim 1. The cardiovascular impact of correcting insulin resistance in obese mice will be determined in Aim 2, using blood flow, blood pressure and vascular remodeling as endpoints. While preliminary data provides novel evidence that insulin resistance and cardiovascular dysfunction are linked, the nature of this relationship is unclear. High levels of HbA1c in obese mice suggest an environment favorable to non-enzymatic glycation and this association is strengthened by the increased expression of the Receptor for Advanced Glycation End-products (RAGE). Both deficits are corrected in obese PTP1B null mice with improved insulin resistance. This leads us to the hypothesis that RAGE is the mechanistic link between insulin resistance and cardiovascular dysfunction and this hypothesis will be tested in Aim 3 by the generation of novel dual KO mice, obese mice lacking RAGE. Taken together, these studies will generate new information about the mechanisms, mediators and physiologic impact of obesity-induced metabolic dysfunction. Successful completion of these aims may identify new targets to aid in the treatment of the most common clinical outcomes of obesity. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the greatest health threat in the obese population, in part due to the metabolic dysfunction that accompanies obesity. Studies proposed in the application identify two new therapeutic targets, PTP1B and RAGE, that may uncouple the deleterious relationship between obesity and cardiovascular disease by breaking the "metabolic connection". Completion of these experiments will not only potentially validate these new targets but also better clarify why obesity causes cardiovascular disease.