Metabolic Determinants of Cardiovascular Dysfunction in Obesity

描述（由申请人提供）：继发于心血管疾病的发病率和死亡率是肥胖患者的主要健康问题。肥胖患者负担着一系列与超重相关的代谢功能障碍。其中最值得注意的是胰岛素抵抗，其导致血浆化学的有害变化、胰岛素的代偿性过度产生以及胰腺2细胞和2型糖尿病的最终衰竭。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，以及代谢和心血管疾病之间的联系机制尚不清楚。在本申请的初步数据中，我们已经产生了一种新的小鼠模型，其中胰岛素受体脱敏基因，蛋白酪氨酸磷酸酶1B（PTP 1B）从肥胖小鼠中删除。结果是一只持续肥胖的小鼠，外周胰岛素抵抗得到纠正。肥胖小鼠在体外显示微血管内皮NO介导的血管舒张功能受损，PTP 1B缺失可纠正这一缺陷。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目标1中确定。将在目标2中使用血流量、血压和血管重塑作为终点来确定肥胖小鼠中校正胰岛素抵抗的心血管影响。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是相关的，但这种关系的性质尚不清楚。肥胖小鼠中高水平的HbA 1c表明有利于非酶糖化的环境，并且这种关联通过晚期糖化终产物受体（Receptor for Advanced Glycation End-products，RGP）的表达增加而得到加强。在具有改善的胰岛素抵抗的肥胖PTP 1B敲除小鼠中，这两种缺陷都得到纠正。这使我们产生了这样的假设，即胰岛素抵抗和心血管功能障碍之间的机制联系是胰岛素抵抗和心血管功能障碍之间的机制联系，并且该假设将在目标3中通过产生新的双重KO小鼠，即缺乏胰岛素抵抗的肥胖小鼠来测试。总之，这些研究将产生新的信息的机制，介质和生理影响的肥胖引起的代谢功能障碍。这些目标的成功完成可能会发现新的目标，以帮助治疗最常见的肥胖症的临床结果。公共卫生相关性：心血管疾病是肥胖人群中最大的健康威胁，部分原因是伴随肥胖的代谢功能障碍。该申请中提出的研究确定了两个新的治疗靶点，PTP 1B和PTP 1B，它们可以通过打破“代谢联系”来解除肥胖和心血管疾病之间的有害关系。这些实验的完成不仅可能验证这些新目标，而且还能更好地阐明肥胖导致心血管疾病的原因。

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.