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

早期生活压力对肥胖小鼠高血压的影响

• 批准号: 10307577
• 负责人: Analia Loria
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307577
• 关键词: Acute; Adipose tissue; Adult; Affect; Afferent Neurons; American; Angiotensin II; Angiotensinogen; Autonomic ganglion; Baroreflex; Biological Assay; Birth; Blood Pressure; Body mass index; Capsaicin; Cardiovascular Diseases; Catecholamines; Child; Chronic; Dose; Exposure to; Feedback; Female; Gene Expression; Generations; Glomerular Filtration Rate; Glucocorticoids; Health; High Fat Diet; Homeostasis; Hormones; Hypertension; Hypothalamic structure; Immediate-Early Genes; Kidney; Knockout Mice; Leptin; Life; Link; Longevity; Mediating; Mediator of activation protein; Metabolic; Microinjections; Modeling; Morbidity - disease rate; Mus; Myocardial Ischemia; Nerve; Nerve Fibers; Neuraxis; Neurons; Nociceptors; Norepinephrine; Obesity; Organ; Outcome Study; Pathway interactions; Personal Satisfaction; Plasma; Procedures; Reflex action; Renal Hypertension; Renin-Angiotensin System; Resiniferatoxin; Risk Factors; Role; Scheme; Sensory; Signal Transduction; Source; Stimulus; Sympathetic Nervous System; Tamoxifen; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Visceral; Weaning; abuse neglect; afferent nerve; analog; base; blood pressure control; blood pressure elevation; blood pressure reduction; blood pressure regulation; brain tissue; cardiovascular risk factor; chromatin immunoprecipitation; comorbidity; diet-induced obesity; early life stress; epidemiologic data; epidemiology study; experimental study; hypertension prevention; in vivo; indexing; kidney dysfunction; leptin receptor; male; maternal obesity; maternal separation; modifiable risk; molecular marker; mortality; mouse model; neglect; neonate; neurotransmission; next generation; novel; paraventricular nucleus; postnatal; prevent; promoter; response; somatosensory; stressor; urinary

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.

项目总结/摘要 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 与早年生活压力有关，是体重指数和血压升高的可改变风险因素。使用 结合产后母体分离和早期生活应激的有利小鼠模型 断奶（MSEW）与高脂肪饮食，我们已经确定了两个潜在的脂肪组织来源的目标 参与这些小鼠显示加重的肥胖诱导的高血压的途径。 实验研究表明，脂肪传入反射（AAR）在饮食诱导的 肥胖模型具体而言，急性刺激脂肪组织传入神经纤维（如辣椒素、瘦素） 升高血压、肾神经活性和血浆儿茶酚胺。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，已经表明脂肪组织特异性 废除唯一的RAS前体，血管紧张素原（AGT），有效地防止高脂饮食诱导的 血压升高。我们的初步研究结果支持新的中心假说产后 MSEW通过刺激AAR反射介导的交感神经来减轻成年期肥胖诱导的HT 激活和脂肪组织来源的AGT分泌。我们将在两个多层次的具体测试中测试关键预测， 目的：（1）验证MSEW通过刺激脂肪代谢而升高肥胖性高血压的假说 组织兴奋性信号以增加AAR反射。我们将评估MSEW对急性AAR反射的影响， 和慢性体内实验，使用新的最先进的技术，以确定脂肪 组织-脑轴对血压的影响;（2）为了检验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。我们会生成一个脂肪组织- 特异性的，他莫昔芬诱导的AGT敲除小鼠，将小鼠暴露于MSEW，并使其在高脂肪 饮食. AGT缺失将在从出生后早期到成年的三个时间点诱导，以 评估其对高血压的编程、进展和逆转的影响。这些研究的结果 可以提供新的早期生活压力程序化的脂肪组织靶点，对血压控制有影响。