Antenatal Steroids Exposure and Adipose Tissue Renin-Angiotensin-System Function

糖皮质激素调节心脏代谢性损害的机制尚不完全清楚。虽然最后一个共同途径可能涉及肾脏，但肾单位数量的减少本身并不能解释血压的升高。在这个项目中，我们将探讨产前类固醇引起心脏代谢损害的另一个机制，即局部脂肪组织肾素血管紧张素系统(RAS)的功能改变，这些改变被肥胖放大，肥胖是一种使平衡向胰岛素抵抗和血压进一步升高倾斜的“二次打击”。工作假说是，产前暴露于类固醇对白色脂肪组织的发育和功能有“编程效应”，并使个体容易患上胰岛素抵抗和高血压。我们进一步假设：1)产前激素暴露改变了白色脂肪组织中局部肾素-血管紧张素系统(RAS)的功能，2)脂肪组织RAS功能异常使个体容易发生心血管和代谢改变，3)肥胖夸大了脂肪组织的功能紊乱，从而增加了产前激素暴露对心血管和代谢调节的影响。肥胖将使用标准的反刍动物配方进行诱导，从而消除了作为混杂因素的饮食中的脂肪成分。绵羊将被随机分配到100%的推荐营养量或临时饲喂三个月。鉴于肥胖的发病率不断增加，以及越来越多的证据表明心血管疾病的发育起源，拟议中的研究将确定肥胖作为一种可改变的危险因素，是否在产前暴露于类固醇的动物中对心血管疾病的发展有重大贡献。我们将通过以下具体目标来检验这些假说：具体目标1：研究产前糖皮质激素暴露对白色脂肪组织(皮下、大网膜和肾周)RAS关键成分和炎症介质表达的影响，以及这些变化对脂肪组织功能的影响。具体目的2：确定胎儿期接触糖皮质激素的动物，脂肪组织中的哪一种成分(S)介导(S)心脏代谢紊乱。具体目的3：研究叠加肥胖加重孕期激素暴露所致心血管和代谢异常的机制。

The mechanism by which glucocorticoids program the cardiometabolic impairment is not completely understood. Although one final common pathway may involve the kidney, the decrease in nephron number, by itself, does not explain the elevation in blood pressure. In this project we will address an additional mechanism by which prenatal steroids cause cardiometabolic impairment, i.e., a functional alteration in the local adipose tissue renin angiotensin system (RAS) and that these alterations are amplified by obesity, a "second hit" that tilts the balance towards insulin resistance and further elevations in blood pressure. The working hypothesis is that antenatal steroid exposure has a "programming effect" on white adipose tissue development and function and predisposes the individual for developing insulin resistance and hypertension. We further hypothesize that 1) antenatal steroid exposure alters the function of a local renin-angiotensin system (RAS) within the white adipose tissue, 2) the abnormal adipose tissue RAS function predisposes the individual for developing cardiovascular and metabolic alterations, 3) Obesity exaggerates the functional derangement of adipose tissue, thus increasing the impact antenatal steroid exposure has on cardiovascular and metabolic regulation. Obesity will be induced using a standard ruminant formula, thus fat composition of the diet is removed as a confounding factor. Sheep of both sexes will be randomly allocated to be fed 100% of recommended nutritional allowance or ad libitum for three months. Given the increasing incidence of obesity and the mounting evidence for a developmental origin of cardiovascular disease, the studies proposed will determine if obesity, a modifiable risk factor, has a significant contribution in the development of cardiovascular diseases in animals exposed antenatally to steroids. We will test these hypotheses with the following specific aims: Specific Aim 1: To study the effects of antenatal glucocorticoid exposure on the expression of critical components of the RAS and inflammatory mediators in white adipose tissue depots (subcutaneous, omental and perirenal) and the consequences these changes have on adipose tissue function. Specific Aim 2: To determine which component(s) of the adipose tissue RAS mediate(s) the cardiometabolic dysregulation in animals exposed antenatally to glucocorticoids. Specific Aim 3: To study the mechanism by which superimposed obesity exaggerates the cardiovascular and metabolic abnormalities induced by antenatal steroid exposure.