Cortisol regulation of perinatal adipose tissue and sheep neonatal leptin peak

描述(申请人提供)：瘦素，作用于下丘脑的食欲中枢，抑制食物摄取。在新生儿、缺氧性啮齿动物出生后一天(PND)8-21瘦素峰值程序平衡食欲和厌食的下丘脑中枢。这一峰值在肥胖大鼠的后代中被放大和延长(关闭)。在早熟物种、人类或重要的农场动物中，还没有关于新生儿瘦素的全面研究。我们的绵羊饮食诱导的母体肥胖(MO)模型增加了成年人的食欲和肥胖症。我们描述了正常饲喂母羊(C-Off)和正常饲喂母羊(C-Off)的新生儿瘦素峰值，以及血浆皮质醇、胰岛素、IGF1、T3和血糖。与新生儿皮质醇升高相关的F1和F2MO-OFF中C-OFF瘦素峰值均被消除。假设：1.皮质醇是独立出生后生命中组织成熟的主要协调者，在围产儿中起着核心作用。 脂肪组织成熟和C-Off新生儿瘦素的调节；2)围产期增加MO-Off皮质醇诱导脂肪组织提前成熟并消除C-Off瘦素峰值；3)模仿C-Off围产期皮质醇增加成人食欲和肥胖。我们还假设不存在性别特异性。方法：18月龄瘦肉、形态均一、未分娩的母羊随机分为：1)C组：母羊孕前、孕中、孕后100%饲喂；(2)MO组，配种前60d、孕中、孕后饲喂150%日粮。实验：我们将研究10组胎儿：1)生理盐水输注C胎儿；2)生理盐水输注MO胎儿；3)长期皮质醇输注C胎儿以模拟MO胎儿皮质醇；4)短期皮质醇输注133d胎龄C胎儿96h分娩。三个自然出生的新生儿组，研究到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)皮质醇-C新生儿给予皮质醇模拟新生儿MO皮质醇；三个成人组，因为我们现在显示在MO中胎儿皮质醇增加，成人研究更清楚，8)生理盐水注入C，9)生理盐水注入MO，和10)长期皮质醇注入C，作为胎儿导尿管，然后研究出生后允许分娩和研究从出生到PND 9，哺乳，断奶，用瘦素敏感性试验进行评估，并在成人生活中研究喂养挑战。终点：血浆瘦素、皮质醇、T3、胰岛素、IGF1和血糖及体外脂肪组织功能、mRNA和蛋白质产物。响应性：绵羊是唯一一种允许将全生命过程研究与胎儿器具相结合的物种，对双重目的、双重利益目标做出了响应，为人类产科和儿科做出了贡献，也是一种重要的食物和羊毛资源。PIS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相关：我们阐述了围产期皮质醇对脂肪组织的作用机制，以1)在妇女帮助诊断、预防和治疗当前人类MO疫情中不良的MO结局；2)在绵羊中，提供对饲料效率和肉类质量至关重要的生物信息。

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.