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: 7753235
• 负责人: Charles A Ducsay
• 金额: $ 30.37万
• 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/7753235
• 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; Face; Fetal Growth Retardation; Fetus; Genes; Gestational Age; Glucocorticoids; Growth; Hydrocortisone; Hypothalamic structure; Hypoxia; In Vitro; Indium; Labor Onset; Laboratories; Leptin; Life; Maintenance; Mediating; Modeling; Neonatal; Newborn Infant; Organ; 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; public health relevance; 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，对胎儿存活和健康构成威胁。然而，胎儿在妊娠过程中具有显著的适应慢性或长期缺氧（LTH）条件的能力，并且胎儿HPA轴代表了适应LTH的重要因素。我们的实验室已经开发了一种LTH模型，其中怀孕母羊保持在高海拔（3，820 m），导致从妊娠第30天开始持续的中度缺氧状态。我们已经表明，胎羊的HPA轴经历了显着的适应性反应LTH。这种适应包括增强的垂体前叶处理POMC ACTH 1 -39，增加基础血浆ACTH 1 -39，并响应于次级应激，增强ACTH 1 -39的释放。LTH胎儿的肾上腺皮质也适应LTH，包括关键类固醇生成酶（CYP 17和CYP 11 A1）的表达减少。累积起来，这些看似矛盾的适应下丘脑-垂体与HPA轴的肾上腺皮质成分导致基础皮质醇水平的维持，但更大的皮质醇生产，以响应LTH胎儿的次级应激。虽然在LTH胎儿的下丘脑-垂体成分水平上观察到的功能增加与短期缺氧对胎儿HPA功能的已知刺激作用一致，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已经调用了一种机制，该机制在面对升高的基础ACTH 1 -39时防止肾上腺皮质过早成熟，但在对危及生命的次级应激源作出反应时允许增加皮质醇的产生。HPA轴对LTH的这些适应可能有助于受损LTH胎儿的存活，同时防止缺氧条件下的早产。调节HPA轴适应LTH的机制仍有待阐明。我们新的初步数据表明：1）白色脂肪组织中瘦素表达增强，血浆瘦素浓度升高; 2）妊娠晚期LTH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表明瘦素拮抗剂在肾上腺皮质水平而非下丘脑-垂体水平的显著作用。因此，瘦素似乎是阻止肾上腺皮质对在LTH胎儿中观察到的升高的基础ACTH 1 -39作出反应的关键因子。在成年人中，瘦素是一种缺氧诱导基因，并已被明确证明可以改变HPA功能。拟议的研究将测试的总体假设，即在LTH胎儿中观察到的增强的瘦素产生在调节HPA轴的巨大变化中起着关键作用，HPA轴允许胎儿适应长期缺氧的压力，但仍保留对急性压力作出反应的能力。公共卫生相关性：拟议的研究对我们基本了解胎儿对慢性应激的适应机制至关重要。从这些研究的结果也将有很大的潜力，了解生理基础的临床问题，如发育迟缓，宫内生长迟缓，疾病在胎儿和新生儿，产前“编程”的胎儿发展疾病作为一个成年人，和隐匿性疾病，发生在高海拔地区。