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

项目摘要/摘要 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 将早年生活压力作为体重指数和血压增加的可改变的风险因素。使用 结合出生后母体分离和早期生活应激的有利小鼠模型 断奶(MSEW)与高脂饮食，我们已经确定了两个潜在的脂肪组织来源的靶点 与这些小鼠表现出加重肥胖诱导的高血压的途径有关。 实验研究表明，饮食诱导的脂肪传入反射(AAR)增强 肥胖模型。具体来说，脂肪组织传入神经纤维(如辣椒素、瘦素)的急性刺激 升高血压、肾神经活动和血浆儿茶酚胺。脂肪组织也表达 肾素血管紧张素系统(RAS)的组成部分。值得注意的是，研究表明，脂肪组织特异性 取消唯一的RAS前体血管紧张素原(AGT)可有效防止高脂饮食诱导的 血压升高。我们的初步发现支持出生后新的中枢假说 MSEW通过刺激AAR反射介导的交感神经加重肥胖诱导的成年生活中的高血压 活化和脂肪组织来源的AGT分泌。我们将在两个多级别的具体实例中测试关键预测 目的：(1)验证MSEW通过刺激脂肪增加肥胖引起的高血压的假设 组织兴奋性信号增加AAR反射。我们将评估MSEW对急性发作时AAR反射的影响。 和慢性活体实验使用一种新的最先进的技术，以确定脂肪 组织-脑轴对血压的影响；以及(2)检验MSEW加剧肥胖的假设- 通过增加脂肪组织中AGT的分泌来诱导高血压。我们将产生一种脂肪组织- 特定的他莫昔芬诱导的AGT基因敲除小鼠，暴露于MSEW并用高脂肪断奶 节食。AGT缺失将在从出生早期到成年的三个时间点被诱导，以便 评估其对高血压的规划、进展和逆转的影响。这些研究的结果 可能提供新的生命早期应激程序性脂肪组织靶点，对血压控制产生影响。

PROJECT SUMMARY/ABSTRACT 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. Experimental studies have demonstrated that adipose afferent reflex (AAR) is enhanced in diet-induced obesity models. Specifically, the acute stimulation of adipose tissue afferent nerve fibers (e.g. capsaicin, leptin) elevates blood pressure, renal nerve activity and plasma catecholamines. Adipose tissue also expresses components of the renin-angiotensin system (RAS). Notably, it has been shown that adipose tissue-specific abrogation of the sole RAS precursor, angiotensinogen (AGT), effectively prevents high fat diet-induced increases in blood pressure. Our preliminary findings support for the novel central hypothesis postnatal MSEW aggravates obesity-induced HT in adult life by stimulating AAR reflex-mediated sympathetic activation and adipose tissue-derived 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. We will assess the effects of MSEW on AAR reflex in acute and chronic in vivo experiments using a novel state of the art technique, in order to determine the adipose tissue-brain axis effects on blood pressure; and (2) To test the hypothesis that MSEW exacerbates obesity- induced hypertension by increasing AGT secretion in adipose tissue. We will generate an adipose tissue- specific, tamoxifen-inducible AGT knockout mouse, expose the mice to MSEW and wean them on a high fat diet. The AGT deletion will be induced at three time points from early postnatal life to adulthood, in order to assess its effects on programming, progression and reversion of hypertension. The outcomes of these studies may provide novel early life stress-programmed adipose tissue targets with impact on blood pressure control.