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: 8408784
• 负责人: Charles A Ducsay
• 金额: $ 27.66万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8408784
• 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.

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，对胎儿生存和健康构成威胁。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）的能力，胎儿HPA轴是适应LTH的重要因素。我们的实验室开发了一种LTH模型，在该模型中，怀孕的母羊被维持在高海拔（3820米），导致从妊娠第30天起持续的中度缺氧状态。我们已经证明，胎羊的下丘脑轴在LTH的反应中经历了显著的适应。这种适应包括垂体前叶POMC对ACTH1-39的加工增强，基础血浆ACTH1-39增加，以及作为对次级应激源的反应，ACTH1-39释放增强。LTH胎儿的肾上腺皮质也适应LTH，包括降低关键类固醇生成酶（CYP17和CYP11A1）的表达。累积起来，这些看似矛盾的适应在下丘脑-垂体和肾上腺皮质的HPA轴组成部分导致维持基础皮质醇水平，但在LTH胎儿对次级应激源的反应中产生更多的皮质醇。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已知的短期缺氧对胎儿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激活了一种机制，该机制在面对基础ACTH1-39升高时防止肾上腺皮质过早成熟，但在面对危及生命的二次应激源时允许增加皮质醇的产生。这些HPA轴对LTH的适应可能有助于LTH受损胎儿的存活，同时防止缺氧条件下的早产。调节HPA轴对LTH的适应性的机制仍有待阐明。我们新的初步数据表明：1)白色脂肪组织中瘦素表达增强，血浆中瘦素浓度升高；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不是下丘脑-垂体水平具有显著作用。因此，瘦素似乎是阻止肾上腺皮质对LTH胎儿中观察到的基础ACTH1-39升高做出反应的关键因素。在成人中，瘦素是一种缺氧诱导基因，已被清楚地证明可以改变HPA功能。这些研究将验证这样一个假设，即在LTH胎儿中观察到的瘦素分泌增强在调节HPA轴的剧烈变化中起关键作用，HPA轴使胎儿适应长期缺氧的压力，同时保留对急性应激的反应能力。