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）：胎儿缺氧是对临床上相关的主要压力源，代表对胎儿生存和福祉的威胁。然而，胎儿具有适应妊娠过程中慢性或长期缺氧（LTH）条件的显着能力，胎儿HPA轴代表了适应LTH的重要元素。我们的实验室开发了一种LTH模型，其中孕妇的母羊保持在高海拔（3,820 m）的高度，从而从妊娠30天开始持续，中度低氧状态。我们已经表明，胎儿绵羊的HPA轴对LTH进行了显着适应。这种适应包括增强了POMC对ACTH1-39的前垂体加工，基础等离子体ACTH1-39的增加，以及响应于次级应激源，增强了ACTH1-39的释放。 LTH胎儿的肾上腺皮质也适应了LTH，包括关键类固醇生成酶的表达降低（CYP17和CYP11A1）。累积地，在HPA轴的下丘脑 - 垂体与肾上腺皮质成分中，这些看似矛盾的适应导致基础皮质醇水平维持较大的皮质醇水平，而皮质醇的产生却更高，响应于LTH胎儿的二级应激源。尽管在LTH胎儿的下丘脑 - 垂体成分水平上观察到的功能的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自适应变化似乎是悖论性的。因此，我们假设LTH调用了一种机制，该机制在面对升高的基底ACTH1-39时可以防止肾上腺皮质过早成熟，但可以增加皮质醇的产生，以响应危及生命的次要压力源。 HPA轴响应于LTH的这些适应可能有助于受损的LTH胎儿的存活，同时防止对低氧条件的早产。响应于LTH的HPA轴介导适应的机制仍有待阐明。我们的新型初步数据表明1）在白色脂肪组织中增强了瘦素表达和血浆瘦素浓度升高2）在晚期妊娠LTH绵羊胎儿的肾上腺中增加瘦素受体表达的增加，而3）新的初步数据清楚地表明了在肾小球级别上的瘦素拮抗剂的戏剧性作用，而不是肾小球级别的pertip级，但不适合使用。因此，瘦素似乎是阻止肾上腺皮质对LTH胎儿观察到的基底ACTH1-39反应的关键药物。在成年人中，瘦素是一种低氧诱导的基因，已清楚地证明可以改变HPA功能。拟议的研究将检验总体假设，即在LTH胎儿中观察到的增强的瘦素产生在调节HPA轴的急剧变化方面起着关键作用，这使得胎儿能够适应长期缺氧但保留对急性应激的能力。