Cortisol regulation of perinatal adipose tissue and sheep neonatal leptin peak

皮质醇对围产期脂肪组织和绵羊新生儿瘦素峰值的调节

• 批准号: 9258462
• 负责人: PETER W. NATHANIELSZ
• 金额: $ 30万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258462
• 关键词: AIDS diagnosis; Address; Adipose tissue; Adult; Adult Children; Affect; Age; Agriculture; Animal Experimentation; Animal Model; Animals; Appetite Stimulants; Back; Biological; Biology; Birth; Blood Vessels; Body Composition; Body Weight; Brain; Breeding; Caring; Catheterization; Catheters; Cell Differentiation process; Cell division; Childhood; Chronic Disease; Colostrum; Data; Dependence; Deposition; Desire for food; Development; Diagnosis; Diagnostic; Diet; Discipline of obstetrics; Eating; Economics; Epidemic; Equilibrium; Fatty acid glycerol esters; Fetus; Food; Glucocorticoid Receptor; Glucocorticoids; Glucose; Goals; Harvest; Health; Hormones; Human; Hydrocortisone; Hypothalamic structure; IGF1 gene; In Vitro; Infusion procedures; Insulin; Intake; Intra-abdominal; Intramuscular; Laboratories; Lead; Leptin; Life; Life Cycle Stages; Lipids; Livestock; Longevity; Matched Group; Meat; Messenger RNA; Metabolism; Milk; Modeling; NIH Program Announcements; Neonatal; Nulliparity; Nutrient; Obesity; Operative Surgical Procedures; Outcome; Paper; Pathway interactions; Pediatrics; Perinatal; Phenotype; Plasma; Play; Pregnancy; Prevention; Procedures; Production; Proteins; Publishing; Randomized; Rattus; Regulation; Resources; Rodent; Role; Saline; Sampling; Sheep; Signal Transduction; Site; Source; Specificity; Testing; Therapeutic; Thinness; Time; Tissues; Triiodothyronine; Weaning; Weight Gain; Woman; Wool; Work; abdominal fat; evidence base; experience; experimental study; feeding; fetal; food quality; in vivo; increased appetite; innovation; instrumentation; man; maternal obesity; neonate; novel; offspring; postnatal; pregnant; premature; prenatal; programs; public health relevance; relating to nervous system; response; sex; skills

DESCRIPTION (provided by applicant): Leptin, acts on hypothalamic appetitive centers to inhibit food intake. In neonatal, altricial rodents a postnatal day (PND) 8 - 21 leptin peak programs balance of orexigenic and anorexigenic hypothalamic centers. The peak is amplified and prolonged in obese rat offspring (OFF). No comprehensive studies on neonatal leptin exist in precocial species, humans or important farm animals. Our sheep model of diet-induced maternal obesity (MO) increases adult OFF appetite and adiposity. We have characterized the neonatal leptin peak in OFF of control (C) normally fed ewes (C-OFF) and MO-OFF and plasma cortisol, insulin, IGF1, T3 and glucose. The C-OFF leptin peak was eliminated in both F1 and F2 MO-OFF associated with higher neonatal cortisol. HYPOTHESES: 1. cortisol, the major coordinator of tissue maturation for independent post-natal life, plays a central role in perinatal adipose tissue maturation and regulation of C-OFF neonatal leptin; 2) increased MO-OFF perinatal cortisol induces premature adipose tissue maturation and eliminates the C-OFF leptin peak; 3) mimicking MO-OFF perinatal cortisol in C-OFF increases adult appetite and adiposity. We also hypothesize OFF sex specificity. APPROACH: Lean 18 month, morphometrically homogeneous, nulliparous ewes are randomly assigned as: 1) C; ewes fed 100% diet pre-, during and after pregnancy or 2) MO, ewes fed 150% diet from 60 d before breeding, during and after pregnancy. Experiments: We will study ten groups: Four fetal groups, vascular catheters placed at 127 and terminated at 147 days gestation (dG) - 1) saline infused C-fetuses; 2) saline infused MO-fetuses; 3) long term cortisol infused C-fetuses to mimic MO fetal cortisol; 4) short term cortisol infused C-fetuses from 133 dG to produce delivery in 96h. Three neonatal groups born spontaneously, studied to PND 9: 5) C-neonates given saline; 6) MO-neonates given saline; 7) Cortisol-C neonates given cortisol to mimic neonatal MO cortisol; Three adult groups, since we now show increased fetal cortisol in MO the adult studies are clearer, 8) saline infused C, 9) saline infused MO, and 10) long-term cortisol infused C, catheterized as fetuses and then studied post-natally allowed to deliver and studied from birth to PND 9, suckled, weaned, evaluated with a leptin sensitivity test and studied in a feeding challenge in adult life. Endpoint: plasma leptin, cortisol, T3, insulin, IGF1 and glucose and in vitro adipose tissue function, mRNA and protein products. RESPONSIVENESS: the sheep is the only species permitting combined full life-course studies with fetal instrumentation, responsive to the Dual Purpose, Dual Benefit goal, contributing to human obstetrics and pediatrics and an important food and wool resource. PIs bring complementary surgical and laboratory skills and experience. RELEVANCE TO THE NATION'S HEALTH AND FARM ANIMALS: We address mechanisms of perinatal cortisol action on adipose tissue to 1) in women aid diagnosis, prevention and treatment of poor MO OFF outcomes in the current human MO epidemic; 2) in sheep, provide the biological information essential to feed efficiency and meat quality.

描述（由申请人提供）：瘦素作用于下丘脑食欲中枢，抑制食物摄入。在新生儿、晚熟啮齿类动物中，出生后 8 - 21 天的瘦素峰值可调节食欲和厌食下丘脑中枢的平衡。在肥胖大鼠后代中，该峰值被放大并延长（OFF）。目前尚无针对早熟物种、人类或重要农场动物的新生儿瘦素的全面研究。我们的饮食引起的母体肥胖 (MO) 绵羊模型会增加成年 OFF 食欲和肥胖。我们已经表征了正常喂养母羊 (C-OFF) 和 MO-OFF 对照 (C) OFF 中的新生儿瘦素峰值以及血浆皮质醇、胰岛素、IGF1、T3 和葡萄糖。 F1 和 F2 MO-OFF 中与新生儿皮质醇较高相关的 C-OFF 瘦素峰值均被消除。假设： 1. 皮质醇是独立产后生活组织成熟的主要协调者，在围产期发挥着核心作用 脂肪组织的成熟和C-OFF新生儿瘦素的调节； 2) MO-OFF围产期皮质醇增加诱导脂肪组织过早成熟并消除C-OFF瘦素峰值； 3）在C-OFF中模仿MO-OFF围产期皮质醇会增加成人食欲和肥胖。我们还假设关闭性别特异性。方法：18 个月瘦肉、形态均匀、未产母羊被随机分配为：1) C；母羊在怀孕前、怀孕期间和怀孕后饲喂 100% 饲料，或 2) MO，母羊从配种前、怀孕期间和怀孕后 60 天开始饲喂 150% 饲料。实验：我们将研究十组：四个胎儿组，血管导管放置在 127 处并在妊娠 147 天（dG）时终止 - 1）注射生理盐水的 C 胎儿； 2) 输注生理盐水的MO-胎儿； 3) 长期向C胎儿注入皮质醇以模拟MO胎儿皮质醇； 4) 从 133 dG 开始短期注射皮质醇，C 胎儿可在 96 小时内分娩。三个自然出生的新生儿组，研究至 PND 9：5) C-新生儿给予生理盐水； 6) MO-新生儿给予生理盐水； 7) 给予 Cortisol-C 新生儿皮质醇以模拟新生儿 MO 皮质醇；三个成人组，因为我们现在显示 MO 中胎儿皮质醇增加，所以成人研究更清楚，8）注射生理盐水 C，9）注射生理盐水 MO，和 10）长期注射皮质醇 C，作为胎儿插入导管，然后研究出生后允许分娩并研究从出生到 PND 9，哺乳，断奶，用瘦素敏感性测试进行评估并在成年生活中进行喂养挑战研究。终点：血浆瘦素、皮质醇、T3、胰岛素、IGF1 和葡萄糖以及体外脂肪组织功能、mRNA 和蛋白质产物。响应性：绵羊是唯一允许将完整生命历程研究与胎儿仪器相结合的物种，响应双重目的、双重利益目标，为人类产科和儿科做出贡献，也是重要的食物和羊毛资源。 PI 带来了互补的外科和实验室技能和经验。与国家健康和农场动物的相关性：我们探讨围产期皮质醇对脂肪组织的作用机制，以：1）在妇女中帮助诊断、预防和治疗当前人类 MO 流行病中 MO OFF 不良结果； 2) 在绵羊中，提供对饲料效率和肉质至关重要的生物信息。

项目成果

Cardiovascular consequences of maternal obesity throughout the lifespan in first generation sheep.

• DOI: 10.1371/journal.pone.0274214
• 发表时间: 2022
• 期刊: PLOS ONE
• 影响因子: 3.7
• 作者: Pankey, Christopher L.;Wang, Qiurong;King, Jessica;Ford, Stephen P.
• 通讯作者: Ford, Stephen P.

Effects of maternal obesity in an ovine model on metabolic outcomes in F2 adults and F3 neonates.

• DOI: 10.1016/j.domaniend.2021.106628
• 发表时间: 2021-07
• 期刊: Domestic animal endocrinology
• 影响因子: 2.1
• 作者: Pankey CL;Odhiambo JF;Smith AM;Ford SP
• 通讯作者: Ford SP

Maternal obesity in sheep impairs foetal hepatic mitochondrial respiratory chain capacity.

绵羊母体肥胖会损害胎儿肝线粒体呼吸链的能力。

• DOI: 10.1111/eci.13375
• 发表时间: 2021
• 期刊: European journal of clinical investigation
• 影响因子: 5.5
• 作者: Serafim,TeresaL;Cunha-Oliveira,Teresa;Deus,ClaudiaM;Sardão,VilmaA;Cardoso,InesM;Yang,Shanshan;Odhiambo,JohnF;Ghnenis,AdelB;Smith,AshleyM;Li,Junfei;Nathanielsz,PeterW;Ford,StephenP;Oliveira,PauloJ
• 通讯作者: Oliveira,PauloJ

Maternal obesity in the ewe increases cardiac ventricular expression of glucocorticoid receptors, proinflammatory cytokines and fibrosis in adult male offspring.

• DOI: 10.1371/journal.pone.0189977
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Ghnenis AB;Odhiambo JF;McCormick RJ;Nathanielsz PW;Ford SP
• 通讯作者: Ford SP