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

糖皮质激素调控心脏代谢损伤的机制尚不完全清楚。虽然最后一个共同的途径可能涉及肾脏，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伤的另一种机制，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，这是一种“二次打击”，使平衡向胰岛素抵抗和血压进一步升高倾斜。目前的假设是，产前类固醇暴露对白色脂肪组织的发育和功能有“编程效应”，使个体容易产生胰岛素抵抗和高血压。我们进一步假设1)产前类固醇暴露改变了白色脂肪组织内局部肾素-血管紧张素系统（RAS）的功能，2)异常的脂肪组织RAS功能使个体易发生心血管和代谢改变，3)肥胖加剧了脂肪组织的功能紊乱，从而增加了产前类固醇暴露对心血管和代谢调节的影响。将使用标准的反刍动物配方来诱导肥胖，因此饮食中的脂肪成分不再是一个混杂因素。随机选取雌雄羊，按推荐营养摄入量100%饲喂或随意饲喂，为期3个月。鉴于肥胖的发病率不断上升，越来越多的证据表明心血管疾病起源于发育，提出的研究将确定肥胖，一个可改变的风险因素，是否在产前暴露于类固醇的动物中心血管疾病的发展中起重要作用。具体目的1：研究产前糖皮质激素暴露对白色脂肪组织库（皮下、网膜和肾周）中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。特定目的2：确定脂肪组织RAS的哪个成分介导了产前暴露于糖皮质激素的动物的心脏代谢失调。具体目的3：研究叠加性肥胖加重产前类固醇暴露引起的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.