Cortisol regulation of perinatal adipose tissue and sheep neonatal leptin peak

描述（由申请方提供）：瘦素，作用于下丘脑食欲中心，抑制食物摄入。在新生儿、晚期啮齿动物中，出生后第8 - 21天（PND）的瘦素峰值可调节下丘脑食欲和食欲中枢的平衡。在肥胖大鼠后代（OFF）中，峰值放大并延长。目前还没有关于早熟物种、人类或重要家畜新生儿瘦素的全面研究。我们的饮食诱导的母体肥胖（MO）的绵羊模型增加了成年人的OFF食欲和肥胖。我们已经表征了对照组（C）正常喂养母羊（C-OFF）和MO-OFF中的新生儿瘦素峰以及血浆皮质醇、胰岛素、IGF 1、T3和葡萄糖。C-OFF瘦素峰在F1和F2 MO-OFF中均被消除，这与新生儿皮质醇较高有关。假设：1.皮质醇是独立的产后生命组织成熟的主要协调者，在围产期中起着核心作用。 脂肪组织成熟和C-OFF新生儿瘦素的调节; 2）增加的MO-OFF围产期皮质醇诱导脂肪组织过早成熟并消除C-OFF瘦素峰; 3）在C-OFF中模仿MO-OFF围产期皮质醇增加成人食欲和肥胖。我们还假设关闭性别特异性。方法：将18个月的瘦的、形态学上均匀的、未经产的母羊随机分配为：1）C;在怀孕前、怀孕期间和怀孕后饲喂100%饮食的母羊或2）MO，从繁殖前60天开始、怀孕期间和怀孕后饲喂150%饮食的母羊。实验：我们将研究10组：四个胎仔组，血管导管放置在127，并在妊娠147天（dG）终止- 1）生理盐水输注的C-胎仔; 2）生理盐水输注的MO-胎仔; 3）长期皮质醇输注的C-胎仔，以模拟MO胎仔皮质醇; 4）短期皮质醇输注的C-胎仔，从133 dG开始，在96小时内分娩。研究至PND 9的三组自然出生新生儿：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，成人研究更清楚，8）生理盐水输注C，9）生理盐水输注MO，和10）长期皮质醇输注C，在胎儿时插入导管，然后在出生后进行研究，允许分娩，从出生到PND 9进行研究，哺乳，断奶，用瘦素敏感性试验进行评价，并在成年期进行喂养挑战研究。终点：血浆瘦素、皮质醇、T3、胰岛素、IGF 1和葡萄糖以及体外脂肪组织功能、mRNA和蛋白质产物。责任：绵羊是唯一允许将全生命过程研究与胎儿仪器相结合的物种，响应双重目的，双重益处目标，有助于人类产科和儿科学以及重要的食物和羊毛资源。PI带来了互补的手术和实验室技能和经验。与国家健康和农场动物的相关性：我们讨论了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流行病中的不良MO OFF结果; 2）在绵羊中，提供饲料效率和肉类质量所必需的生物信息。

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.