NUTRITIONAL CONTROL OF REPRODUCTIVE AND STRESS AXES

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如何传递到生殖系统。 这一建议是基于我们的观察，即代谢激素，瘦素，在限食期间单独给药维持LH的脉动分泌。限制食物或代谢燃料的条件可以深刻地影响生殖轴。 在这个建议中，我们测试的假设，这些妥协的代谢条件是“感觉”的大脑作为一个“压力”，这是“压力”，导致抑制LH脉冲。 根据这一假说，瘦素通过抑制这种“应激”反应而起作用，从而维持脉冲式LH分泌。 在具体目标一中，我们将确定禁食是否激活应激轴，同时抑制LH脉冲分泌，以及禁食期间给予瘦素是否阻断应激激活和LH脉冲抑制。此外，在这个目标中，我们确定是否室旁核（PVN）以及在其他非PVN CRH网站的CRH神经元调节禁食，如果瘦素逆转这种调节。 在具体目标二中，我们将确定大脑瘦素（免疫中和）的急性减少是否激活应激轴，同时抑制脉冲式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。 进一步在这个目标中，我们将确定那些神经元激活减少脑瘦素（cfos激活），试图确定这些细胞响应这种代谢激素的可用性降低。 最后一项研究，在这个目标，确定了神经肽表型的cfos激活细胞由于减少大脑瘦素。 使用这些解剖学数据与CRH的数据，我们希望确定神经肽系统响应减少脑瘦素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）是否直接或间接投射到GnRH神经元。该项目与人类健康有关，因为它解决了由脂肪激素瘦素调节的潜在机制和解剖学途径，瘦素是一种对许多神经内分泌系统正常运作至关重要的激素。 这项工作应有助于解释的基础上，神经内分泌功能的干扰，在几种代谢紊乱，以及提供深入了解内分泌的复杂性，观察到的几种动物模型的肥胖。

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.