Leptin and hypothalamo-pituitary-adrenal function in the long-term hypoxic fetus

胎儿长期缺氧时瘦素与下丘脑-垂体-肾上腺功能的关系

• 批准号: 8018534
• 负责人: Charles A Ducsay
• 金额: $ 29.15万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8018534
• 关键词: Adipose tissue; Adrenal Cortex; Adrenal Glands; Adult; Altitude; Anabolism; Anterior Pituitary Gland; Attenuated; Birth; CYP11A1 gene; CYP17A1 gene; Chronic; Chronic stress; Clinical; Corticotropin; Coupled; Data; Development; Disease; Enzymes; Fetal Growth Retardation; Fetus; Genes; Gestational Age; Glucocorticoids; Growth; Health; Hydrocortisone; Hypothalamic structure; Hypoxia; In Vitro; Indium; Labor Onset; Laboratories; Leptin; Life; Maintenance; Mediating; Modeling; Neonatal; Newborn Infant; Organ; Personal Satisfaction; Physiological; Pituitary Gland; Plasma; Play; Pregnancy; Premature Birth; Process; Production; Recombinants; Role; Sheep; Stress; Testing; Work; acute stress; base; clinically relevant; fetal; fetus hypoxia; in vivo; leptin receptor; novel; pregnant; premature; prenatal; prevent; programs; receptor expression; response; stressor

DESCRIPTION (provided by applicant): Fetal hypoxia is a major clinically relevant stressor representing a threat to fetal survival and well- being. However, the fetus has the remarkable ability to adapt to conditions of chronic or long-term hypoxia (LTH) over the course of gestation and the fetal HPA axis represents an important element in the adaptation to LTH. Our laboratory has developed a model of LTH in which pregnant ewes are maintained at high altitude (3,820 m) resulting in a sustained, moderate hypoxic state from day 30 of gestation onward. We have shown that the HPA axis of fetal sheep undergoes significant adaptation in response to LTH. This adaptation includes enhanced anterior pituitary processing of POMC to ACTH1-39, increased basal plasma ACTH1-39 and, in response to a secondary stressor, enhanced ACTH1-39 release. The adrenal cortex of the LTH fetus also adapts in response to LTH including a reduced expression of key steroidogenic enzymes (CYP17 and CYP11A1). Cumulatively, these seemingly contradictory adaptations in the hypothalamo-pituitary vs. adrenocortical components of the HPA axis result in maintenance of basal cortisol levels yet greater cortisol production in response to a secondary stressor in the LTH fetus. While the increased function observed at the level of the hypothalamic-pituitary component in the LTH fetus is consistent with the known stimulatory actions of short-term hypoxia on fetal HPA function, the adaptive changes observed at the level of the adrenal cortex seem paradoxical. Thus, we hypothesize that LTH has invoked a mechanism(s) that prevents premature maturation of the adrenal cortex in the face of elevated basal ACTH1-39 yet allows increased cortisol production in response to a life-threatening secondary stressors. These adaptations in the HPA axis in response to LTH likely aid in the survival of the compromised LTH fetus while preventing preterm delivery in response to the hypoxic condition. The mechanisms mediating adaptation of the HPA axis in response to LTH remain to be elucidated. Our novel preliminary data demonstrate 1) enhanced leptin expression in white adipose tissue and elevated plasma leptin concentrations 2) increased leptin receptor expression in the adrenal gland of the late gestation LTH sheep fetus and 3) new preliminary data clearly showing the dramatic effects of a leptin antagonist at the level of the adrenal cortex but not at the hypothalamic-pituitary level. Thus, leptin appears to be a key agent preventing the adrenal cortex from responding to the elevated basal ACTH1-39 observed in the LTH fetus. In adults, leptin is a hypoxia-inducible gene and has clearly been demonstrated to alter HPA function. The proposed studies will test the overall hypothesis that the enhanced leptin production observed in the LTH fetus plays a key role in regulating the dramatic changes in the HPA axis that allow the fetus to acclimatize to the stress of long-term hypoxia yet retain the ability to respond to acute stress. PUBLIC HEALTH RELEVANCE: The proposed studies are critical to our basic understanding of fetal adaptive mechanisms to chronic stress. Results from these studies will also have great potential for understanding the physiologic basis for clinical problems such as delayed development, intrauterine growth retardation, disease in the fetus and newborn, prenatal "programming" of the fetus to develop disease as an adult, and occult diseases that occur at high altitude.

描述(由申请人提供)：胎儿缺氧是一种主要的临床相关应激源，对胎儿的生存和健康构成威胁。然而，胎儿在妊娠过程中对慢性或长期缺氧(LTH)具有显著的适应能力，胎儿HPA轴是适应LTH的重要因素。本实验室建立了妊娠绵羊LTH模型，将妊娠母羊置于海拔3820米的高海拔地区，从妊娠第30天起持续处于中度低氧状态。我们发现胎羊的HPA轴对LTH有明显的适应作用。这种适应包括增强POMC对ACTH1-39的处理，增加基础血浆ACTH1-39，以及作为对次级应激源的反应，增强ACTH1-39的释放。LTH胎儿的肾上腺皮质也会对LTH做出反应，包括关键的类固醇生成酶(CyP17和Cyp11a1)表达减少。总体而言，下丘脑-垂体和HPA轴的肾上腺皮质成分之间的这些看似矛盾的适应导致LTH胎儿维持基础皮质醇水平，同时又产生更多的皮质醇，以应对次级应激源。虽然在LTH胎儿下丘脑-垂体部水平上观察到的功能增强与已知的短期低氧对胎儿HPA功能的刺激作用是一致的，但在肾上腺皮质水平上观察到的适应性变化似乎是矛盾的。因此，我们假设LTH已经激活了一种机制(S)，该机制在基础ACTH1-39升高的情况下防止肾上腺皮质过早成熟，但允许在威胁生命的次要应激源下增加皮质醇的产生。HPA轴对LTH的这些适应可能有助于LTH受损胎儿的存活，同时防止因低氧条件而早产。调节HPA轴适应LTH的机制仍有待阐明。我们新的初步数据显示，1)白色脂肪组织中瘦素表达增加，血浆瘦素浓度升高，2)妊娠晚期绵羊胎儿肾上腺中瘦素受体表达增加，3)新的初步数据清楚地显示了瘦素拮抗剂在肾上腺皮质水平上的显著作用，而不是在下丘脑-垂体水平上的显著作用。因此，瘦素似乎是阻止肾上腺皮质对LTH胎儿基础ACTH1-39升高的反应的关键因素。在成年人中，瘦素是一种低氧诱导基因，已被明确证明可以改变HPA的功能。拟议的研究将检验总体假设，即在LTH胎儿中观察到的瘦素生成增加在调节HPA轴的戏剧性变化方面发挥了关键作用，HPA轴的急剧变化使胎儿能够适应长期缺氧的应激，但仍保持对急性应激的反应能力。公共卫生相关性：拟议的研究对于我们基本理解胎儿对慢性应激的适应机制至关重要。这些研究的结果也将极有可能理解临床问题的生理学基础，如发育迟缓、宫内发育迟缓、胎儿和新生儿的疾病、胎儿作为成年人的产前“规划”疾病以及发生在高海拔地区的隐匿性疾病。