Perinatal Metabolic and Hormonal Effects

描述（由申请人提供）：肥胖和2型糖尿病是一个主要的流行病。10 - 20%的这种流行病是由于宫内/产后营养不良以及随后的西方饮食和久坐不动的生活方式造成的。胎儿/新生儿低胰岛素血症和低肾上腺素血症的营养不良相关因素引发一系列下丘脑适应性事件，最终导致贪食/不活动、内脏肥胖、胰岛素和瘦素抵抗。这种以增强能量摄入和保存能量消耗为目标的有利于生存的产后适应包括下丘脑胰岛素受体、瘦素受体的表达增加，神经肽Y、阿戈提相关肽的表达增加，黑素皮质素-3受体的表达减少。基于这些发现，我们假设产前/产后营养不良永久性地扰乱了下丘脑：1)瘦素和/或胰岛素受体和受体后信号通路；2)通过改变后代的核大小、神经元活动和喂养神经回路来改变结构，从而导致肥胖的发生；3)产后给药可逆转这些改变。为了验证这一假设，我们将使用受产前和产后卡路里限制的大鼠模型，并在断奶后喂食高热量饮食。具体目的包括：通过评估ObRb-JAK2-STAT3/SOCS3-SHP2-PTP1B和irβ酪氨酸激酶- irs1 /2- p -l-3激酶- PDK1/2-Akt1/2/PKC，探讨产前和产后营养限制对雄性和雌性p2-哺乳期、p2-哺乳期、p240-成年或p450-500-衰老成年下丘脑的影响：a)瘦素和胰岛素受体互导信号通路；-PDE38-cAMP途径和b)厌氧（NPY/AgRP）和厌氧（α - msh）神经肽。2。a)通过Niss1染色和定量立体学评估核体积，b)使用c-fos浓度评估核神经元活动，c)通过逆行跟踪从弓形核到室旁、背内侧和外侧下丘脑的神经投射来观察神经馈电回路。3。a)关键瘦素和胰岛素受体和受体后信号，以及b)神经肽（NPY/AgRP和α - msh）的变化，响应于d2至d7期间外源性系统性瘦素的管理，最终表型逆转。我们提出的研究结果将填补我们知识中的重要空白，并为围产期营养扰动导致喂养行为/能量消耗的永久性变化提供分子和细胞基础。

DESCRIPTION (provided by applicant): There is a major epidemic of obesity and type 2 diabetes. Ten-twenty% of this epidemic arises because of in-utero/postnatal malnutrition with subsequent superimposition of western diet and sedentary life style. The undernutrition related factors of fetal/neonatal hypoinsulinemia and hypoleptinemia provoke a cascade of hypothalamic adaptive events, which lend towards a permanency by culminating in hyperphagia/inactivity, visceral adiposity, insulin and leptin resistance. This pro-survival postnatal adaptation targeted at enhancing energy intake and conserving its expenditure consists of an increase in the hypothalamic insulin receptor, leptin receptor expression with an increase in neuropeptide Y, agouti-related peptide expression, and a decrease in melanocortin-3 receptor. Based on these findings, we hypothesize that prenatal/postnatal malnutrition permanently perturbs the hypothalamic 1) leptin &/or insulin receptor and post-receptor signaling pathways, and 2) structure by altering nuclear size, neuronal activity, and feeding neural circuit in the offspring which predates the development of obesity, with 3) a reversal of these alterations with postnatal administration of leptin. To test this hypothesis, we will use the rat model subjected to pre- and postnatal calorie restriction and fed a hypercaloric diet post-weaning. The specific aims consist of exploring the impact of pre- and post-natal nutrient restriction on male and female p2-suckling, p25-post-suckling, p240-adult, or p450-500-aging adult hypothalamic: I. a) leptin and insulin receptor cross-talk signaling pathways by assessing the ObRb-JAK2-STAT3/SOCS3-SHP2-PTP1B and the IRbeta tyrosine kinase-IRS1/2-P-l-3-kinase- PDK1/2-Akt1/2/PKC;-PDE38-cAMP pathways and b) the orexigenic (NPY/AgRP) and anorexigenic (alpha-MSH) neuropeptides. II. a) nuclear volume assessed by Niss1 staining and quantitative stereology, b) nuclear neuronal activity by using c-fos concentrations, and c) the feeding neural circuitary by retrograde tracking of the neural projections from the arcuate nucleus to the paraventricular, dorsomedial, and lateral hypothalamus. III. a) key leptin and insulin receptor and post-receptor signaling, and b) neuropeptide (NPY/AgRP & alpha-MSH) changes, in response to exogenous administration of systemic leptin between d2 to d7, towards reversal of the ultimate phenotype. The results of our proposed investigations will fill vital gaps in our knowledge and provide the molecular and cellular basis for perinatal nutritional perturbations causing permanent changes in feeding behavior/energy expenditure.