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

糖皮质激素调节心脏代谢损伤的机制并不完全 明白了。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， 这本身并不能解释血压的升高。在这个项目中，我们将解决另一个 产前类固醇引起心脏代谢损害的机制，即心脏功能改变 局部脂肪组织肾素血管紧张素系统(RAS)和这些变化被肥胖放大， “二次打击”，使天平向胰岛素抵抗和血压进一步升高倾斜。这个 工作假说是孕期接触类固醇对白色脂肪组织有“编程效应” 发育和功能，并使个体易患上胰岛素抵抗和高血压。 我们进一步假设：1)产前接触类固醇改变了局部肾素-血管紧张素的功能 系统(RAS)在白色脂肪组织内，2)异常的脂肪组织RAS功能易患 发生心血管和代谢改变的个体，3)肥胖夸大功能 脂肪组织紊乱，因此增加了产前类固醇暴露对心血管的影响 和新陈代谢调节。肥胖将使用标准的反刍动物配方诱导，因此脂肪成分 饮食不再是一个混杂的因素。将随机分配给不同性别的绵羊100%饲喂 三个月的推荐营养补充量或临时营养。鉴于发病率不断上升， 肥胖和心血管疾病发育性起源的越来越多的证据，研究 将确定肥胖这一可改变的风险因素是否对疾病的发展有重大贡献 在动物出生前暴露于类固醇的心血管疾病。我们将用以下方法来检验这些假设 以下是具体目标： 具体目的1：研究产前糖皮质激素暴露对关键基因表达的影响 白色脂肪储存库中RAS和炎症介质的成分(皮下、大网膜 和肾周)，以及这些变化对脂肪功能的影响。 特定目的2：确定脂肪组织中的哪一组分(S)介导(S) 胎儿期接触糖皮质激素的动物心脏代谢紊乱。 具体目标3：研究叠加肥胖加重心血管疾病的机制 以及产前接触类固醇引起的代谢异常。 相关性(请参阅说明)： 产前糖皮质激素仍然是降低#年呼吸窘迫综合征风险的唯一替代方案 早产儿。考虑类固醇治疗动物RAS系统的功能上调 而RAS在肥胖和糖尿病患者血压调节中的作用，源于此 一项提案将为确定成年肥胖是否放大已经存在的变化铺平了道路 胎儿期接触糖皮质激素的动物。

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 alterafion in the local adipose tissue renin angiotensin system (RAS) and that these alterafions 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 funcfion 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 regulafion. Obesity will be induced using a standard ruminant formula, thus fat composifion 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 fissue depots (subcutaneous, omental and perirenal) and the consequences these changes have on adipose fissue function. Specific Aim 2: To determine which component(s) of the adipose tissue RAS mediate(s) the cardiometabolic dysregulafion 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. RELEVANCE (See Instructions): Antenatal glucocorticoids remain the single alternative to reduce the risk of respiratory distress syndrome in premature newborns. Considering the functional upregulafion of the RAS system in steroid-treated animals and the role of the RAS in the regulation of blood pressure in obese and diabetic humans, results from this proposal will pave the way for establishing if obesity in adulthood magnifies the alterations already present in animals exposed prenatally to glucocorticoids.