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

摘要/拟议工作范围 肥胖会导致高血压，这是心血管疾病的主要危险因素。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， 产后母亲分离和早期断奶（MSEW）与高脂肪饮食，我们有 确定了两个潜在的脂肪组织来源的目标，涉及的途径， 这些小鼠表现出加重的肥胖诱导的高血压。我们的初步研究结果 支持新的中心假设，即出生后MSEW会抑制肥胖诱导的HT， 成年生活通过刺激脂肪传入反射（AAR）介导的交感神经激活， 脂肪组织来源的血管紧张素原（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增加肥胖诱导的 高血压通过刺激脂肪组织兴奋性信号增加AAR反射。在这 目的是，申请人将有助于确定不同的神经元被激活， 对喂食高脂饮食的MSEW小鼠的反应，并在雌性小鼠体内测试传入反射; 和（2）为了检验MSEW加重肥胖引起的高血压的假设， 增加脂肪组织中AGT的分泌。申请人将参与确定 循环血管紧张素II的变化是否会影响室周肌的激活 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).