NUTRITIONAL CONTROL OF REPRODUCTIVE AND STRESS AXES

生殖轴和应激轴的营养控制

• 批准号: 6381200
• 负责人: ROBERT C THOMPSON
• 金额: $ 13.8万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381200
• 关键词: adrenocorticotropic hormone; corticotropin releasing factor; dietary restriction; fasting; female; female reproductive system; gonadotropin releasing factor; hormone receptor; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; hypothalamic pituitary axis; in situ hybridization; laboratory rat; leptin; luteinizing hormone; messenger RNA; neuroanatomy; neuroendocrine system; neuroregulation; nutrition related tag; ovariectomy; paraventricular nucleus; pituitary gonadal axis; secretion; stress

Our overall goal is determine how endocrine and sensory information associated with altered states of nutrition is relayed to the reproductive system. This proposal is based upon our observation that the metabolic hormone, leptin, administered alone during food restriction maintains pulsatile LH secretion. Conditions which limit food or metabolic fuels can profoundly effect the reproductive axis. In this proposal, we test the hypothesis that these compromised metabolic conditions are "sensed" by the brain as a "stress" and it is this "stress" that leads to an inhibition in LH pulses. According to this hypothesis, leptin acts by inhibiting this "stress" reaction via brain sites thereby maintaining pulsatile LH secretion. In Specific aim one, we will determine if fasting activates the stress axis concurrently with the inhibition of pulsatile LH secretion and if leptin administration during the fasting period blocks the stress activation as well as LH pulse inhibition. Additionally in this aim, we determine if CRH neurons in the paraventricular nucleus (PVN) as well as in other non-PVN CRH sites are regulated by fasting and if leptin reverses this regulation. In Specific aim two, we will determine if acute reductions in brain leptin (immunoneutralization) activate the stress axis while inhibiting pulsatile LH secretion. It also determines if these neuroendocrine changes are mediated by the stress peptide, corticotropin releasing hormone, CRH. Further in this aim, we will identify those neurons activated by reduced brain leptin (cfos activation) in an attempt to identify those cells responding to the reduced availability of this metabolic hormone. The last study in this aim, identifies the neuropeptide phenotype of cfos activated cells due to reductions in brain leptin. Using this anatomical data together with the data on CRH, we expect to identify neuropeptide systems responding to reduced brain leptin and potential mediators of the neuroendocrine changes. In Specific aim three, we will use anatomical tract tracing methods and receptor mRNA colocalization studies to determine if CRH (or other suggested leptin sensitive neuropeptides) project directly or indirectly to GnRH neurons. This project is relevant to human health because it addresses the underlying mechanisms and anatomical pathways that are regulated by the fat hormone leptin, a hormone critical to the proper functioning of many neuroendocrine systems. This work should help explain the basis for disruption of neuroendocrine functions in several metabolic disorders as well as provide insight into understanding the endocrine complexities observed in several animal models of obesity.

我们的总体目标是确定与营养状态改变相关的内分泌和感觉信息是如何传递到生殖系统的。这一建议是基于我们的观察，代谢激素，瘦素，单独给予在食物限制维持脉动性黄体生成素分泌。限制食物或代谢燃料的条件可以深刻地影响生殖轴。在这项提议中，我们测试了这样一个假设，即这些受损的代谢状况被大脑“感知”为“压力”，正是这种“压力”导致了LH脉冲的抑制。根据这一假说，瘦素的作用是通过抑制大脑部位的这种“应激”反应，从而维持脉动性LH分泌。在具体目标一中，我们将确定禁食是否在抑制脉动性LH分泌的同时激活应激轴，以及禁食期间给药瘦素是否阻断应激激活和LH脉冲抑制。此外，在此目的中，我们确定室旁核（PVN）以及其他非PVN CRH位点的CRH神经元是否受禁食调节，以及瘦素是否逆转这种调节。在具体目标二中，我们将确定脑瘦素（免疫中和）的急性减少是否激活应激轴，同时抑制脉动性LH分泌。它还确定这些神经内分泌变化是否由应激肽、促肾上腺皮质激素释放激素（CRH）介导。为了进一步实现这一目标，我们将识别那些被脑瘦素减少激活的神经元（cfos激活），以试图识别那些对这种代谢激素可用性减少做出反应的细胞。最后一项研究，在这个目的，确定神经肽表型的cfo活化细胞由于减少脑瘦素。利用这一解剖学数据和CRH数据，我们希望确定对脑瘦素减少做出反应的神经肽系统和神经内分泌变化的潜在介质。在具体目标三中，我们将使用解剖束追踪方法和受体mRNA共定位研究来确定CRH（或其他建议的瘦素敏感神经肽）是否直接或间接地投射到GnRH神经元。该项目与人类健康相关，因为它解决了由脂肪激素瘦素调节的潜在机制和解剖途径，瘦素是许多神经内分泌系统正常运作的关键激素。这项工作将有助于解释几种代谢紊乱中神经内分泌功能破坏的基础，并为理解在几种肥胖动物模型中观察到的内分泌复杂性提供见解。