Cortisol regulation of perinatal adipose tissue and sheep neonatal leptin peak

描述（申请人提供）：瘦素，作用于下丘脑食欲中枢，抑制食物摄入。在新生儿，晚食啮齿类动物出生后（PND） 8 - 21瘦素峰值程序的平衡食欲和厌氧性下丘脑中心。在肥胖大鼠后代（OFF）中，峰值被放大和延长。在早熟物种、人类或重要家畜中尚无关于新生儿瘦素的全面研究。我们的绵羊饮食诱导的母羊肥胖（MO）模型增加了成年OFF的食欲和肥胖。我们研究了正常喂养母羊（C-OFF）和MO-OFF以及血浆皮质醇、胰岛素、IGF1、T3和葡萄糖的新生儿瘦素峰值。在F1和F2中，与新生儿皮质醇升高相关的C-OFF瘦素峰值被消除。假设:1。皮质醇是独立的产后生活组织成熟的主要协调者，在围产期起着核心作用

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.