Rapid Metabolic Control of the HPG System

描述(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、肥胖症和糖尿病引起的不孕不育和相关并发症(如骨质疏松症)的了解。下丘脑-垂体-性腺(HPG)系统依赖于代谢燃料的供应，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，这些作用在重新摄食后几个小时内被逆转。FR会导致一长串激素、神经肽和代谢事件的变化。重新摄食的快速效应将使我们能够准确定位那些足够快地发生的神经内分泌事件，以解释重新摄食的影响，并忽略具有生殖以外功能的较慢的变化。采用放射免疫分析、免疫细胞化学、原位杂交和推拉灌流等方法，对随意饲喂过的仓鼠和绵羊的血液循环激素(胰岛素、瘦素、生长激素、Ghrelin)和脑神经肽(如神经肽Y和促肾上腺皮质激素释放激素)进行检测。此外，将向FR仓鼠和绵羊补充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。仓鼠一致的、易于监测的四天发情周期使其在阐明发情周期的某些基本要求方面取得了快速进展(美国施耐德实验室)。母羊更大的血液供应将使我们能够测量脉动的促黄体生成素分泌以及广泛的其他激素和代谢底物，以阐明最初刺激促黄体生成素分泌的急性事件(澳大利亚克拉克实验室)。来自两个不同分类群的物种的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.