Effect of early life stress on obesity-induced hypertension in mice

建议的工作摘要/范围 肥胖会促进高血压，高血压是心血管疾病的一个主要风险因素。流行病学 研究表明，早年生活压力是体重指数增加的一个可改变的风险因素 还有血压。使用一种有利的早期生活压力的小鼠模型 产后母体分离和早期断奶(MSEW)通过高脂肪饮食，我们有 确定了两个潜在的脂肪组织来源的靶点，这些靶点涉及到 这些小鼠表现出加重的肥胖诱导的高血压。我们的初步调查结果 支持新的中心假说，即出生后MSEW加重肥胖诱导的高血压 通过刺激脂肪传入反射(AAR)介导的交感神经激活和 脂肪组织源性血管紧张素原(AGT)分泌。我们将在两个方面测试关键预测 多层次的具体目标：(1)检验MSEW加剧肥胖诱导的假设 高血压通过刺激脂肪组织兴奋性信号增加AAR反射。在这 目的，申请者将有助于确定不同的神经元在 对高脂饲料喂养的MSEW小鼠的反应和雌性小鼠体内传入反射的测试； 以及(2)检验MSEW通过以下方式加重肥胖引起的高血压的假设 增加脂肪组织中AGT的分泌。申请者将参与决定 循环血管紧张素II的变化是否影响环室的激活 器官(CVO)。

Abstract/ scope of work proposed Obesity promotes hypertension, a major risk factor for cardiovascular disease. Epidemiological studies have linked early life stress as a modifiable risk factor for increased body mass index and blood pressure. Using an advantageous mouse model of early life stress that combines postnatal maternal separation and early weaning (MSEW) with a high fat diet, we have identified two potential adipose tissue-derived targets implicated in the pathways by which these mice display exacerbated obesity-induced hypertension. Our preliminary findings support the novel central hypothesis that postnatal MSEW aggravates obesity-induced HT in adult life by stimulating adipose afferent reflex (AAR)-mediated sympathetic activation and adipose tissue-derived angiotensinogen (AGT) secretion. We will test key predictions in two multilevel specific aims: (1) To test the hypothesis that MSEW heightens obesity-induced hypertension by stimulating adipose tissue excitatory signals to increase AAR reflex. In this aim, the applicant will contribute to determine the different neurons that are activated in response to MSEW mice fed a high fat diet and test the afferent reflex in vivo in female mice; and (2) To test the hypothesis that MSEW exacerbates obesity-induced hypertension by increasing AGT secretion in adipose tissue. The applicant will contribute to determine whether changes in circulating angiotensin II influence the activation of the circuventricular organs (CVO).