Rapid Metabolic Control of the HPG System

描述（由申请人提供）：这项多学科的国际合作将扩大我们对营养不良、节食、过度运动、神经性厌食症、肥胖和糖尿病引起的不孕症及其相关并发症（如骨质疏松症）的理解。下丘脑-垂体-性腺（HPG）系统依赖于代谢燃料的可用性，但代谢刺激的位置和性质尚不清楚。食物限制（FR）抑制发情周期和黄体生成素（LH）的脉动分泌，这些影响在重新进食后数小时内逆转。FR会导致一长串的激素、神经肽和代谢事件发生变化。再进食的快速影响将使我们能够精确地找出那些发生得足够快的神经内分泌事件，以解释再进食的影响，并忽略那些服务于生殖以外功能的较慢的变化。放射线免疫测定、免疫细胞化学、原位杂交和推拉灌注将用于测量随意饲喂、FR或FR后再饲喂的仓鼠和羊的循环激素（胰岛素、瘦素、生长激素、生长素）和脑神经肽（如神经肽Y和促肾上腺皮质激素释放激素）。此外，FR仓鼠和绵羊将被喂食各种常量营养素和燃料，以确定对快速恢复HPG功能至关重要的代谢刺激。仓鼠连续且易于监测的4天发情周期使得阐明发情周期的某些基本要求取得快速进展（Schneider实验室，美国）。母羊更大的血液供应将使我们能够测量脉动性黄体生成素分泌以及一系列其他激素和代谢底物，以阐明黄体生成素分泌最初刺激的急性事件（Clarke实验室，澳大利亚）。对来自两个不同分类群的物种进行比较将检验结论的普遍性。

DESCRIPTION (provided by applicant): This multidisciplinary, international collaboration will broaden our understanding of infertility and related complications (e.g., osteoporosis) due to undernutrition, dieting, excessive exercise, anorexia nervosa, obesity and diabetes. The hypothalamic-pituitary-gonadal (HPG) system is dependent upon the availability of metabolic fuels, but the location and nature of the metabolic stimuli are unknown. Food restriction (FR) inhibits estrous cycles and pulsatile secretion of luteinizing hormone (LH), and these effects are reversed within hours after refeeding. FR leads to changes in a staggeringly long list of hormones, neuropeptides and metabolic events. The rapid effects of refeeding will allow us to pinpoint those neuroendocrine events that occur rapidly enough to account for the effects of refeeding, and to discount slower changes that serve functions other than reproduction. Radioimmunoassy, immunocytochemistry, in situ hybridization and pushpull perfusion will be used to measure circulating hormones (insulin, leptin, growth hormone, ghrelin) and brain neuropeptides (e.g., neuropeptide Y and corticotropin releasing hormone) in hamsters and sheep that have been either fed ad libitum, FR, or FR and then refed. In addition, FR hamsters and sheep will be refed with various macronutrients and fuels to determine the metabolic stimuli that are critical for rapid restoration of HPG function. The hamster's consistent, easily monitored four-day estrous cycle enables rapid progress in elucidating certain basic requirements for estrous cyclicity (Schneider laboratory, USA). The larger blood supply of the ewe will allow us to measure pulsatile LH secretion along with a wide array of other hormones and metabolic substrates in order to elucidate the acute events that underlie the initial stimulation of LH secretion (Clarke laboratory, Australia). Comparisons of species from two different taxa will test the generality of the conclusions.