Neural basis of leptin action in reproduction

摘要 正常的青春期发育和生殖需要最低量的储存能量 成人生活中的健康另一方面，过多的能量会对生殖生理产生负面影响。 女性肥胖症加重多囊卵巢综合征，排卵功能障碍， 生殖能力。在肥胖的男性中，由于下丘脑的活动改变，生育能力降低- 垂体-性腺（HPG）轴和睾丸中类固醇生成缺陷。儿童死亡率的上升 肥胖与青春期提前及其有害后果有关。女孩月经初潮早 与成人肥胖、2型糖尿病和乳腺癌的风险增加有关。因此，代谢线索 是青春期开始和生殖系统充分运作的基本信号， 成人生活脂肪细胞激素瘦素告知储存到HPG轴的能量的量。人类和 具有瘦素信号传导缺陷的小鼠肥胖且不育，保持在青春期前的状态。虽然 这些突变非常罕见，这对原理证明很重要。人类肥胖与高瘦素血症有关， 而不是瘦素缺乏症肥胖个体对瘦素给药表现出低或无反应，这表明 功能性瘦素抵抗，这有助于由过量能量储存引起的生育缺陷。的 脑定位的分子技术的最新发展和基因修饰小鼠的应用 模型增强了我们对参与代谢控制的大脑部位的理解。但 代谢线索的主要生殖作用的神经基础仍不清楚。本实验室 确定了下丘脑腹侧乳头体前核（PMV）作为瘦素作用的重要中继， 生殖生理学在强有力的初步数据的指导下，我们假设PMV有三个不同的 神经元成分（即，兴奋性，抑制性和同步性），以及它们之间的平衡 决定了HPG轴对代谢线索的反应。这一假设将在三个 独立但互补的目标。在目标1和目标2中，我们将在小鼠中使用病毒遗传学和化学遗传学， 确定谷氨酸神经传递（兴奋成分）和多巴胺作用的模型 转运蛋白表达神经元（抑制成分）在生殖控制。在目标3中，我们将评估 一氧化氮（同步成分）在小鼠PMV神经元网络活动中的作用 遗传学和钙成像这些实验的结果将为生物技术的发展提供新的机会。 了解青春期启动和生殖功能代谢控制的神经基础。 我们的研究结果将允许特定地点的调查的原因和机制的生殖 由代谢紊乱引起的缺陷（例如，肥胖、糖尿病、厌食症），包括青春期提前、排卵障碍 功能障碍、下丘脑性闭经和不孕症。

Abstract A minimum amount of stored energy is required for normal pubertal development and for reproductive health in adult life. On the other hand, excess energy negatively impacts the reproductive physiology. Elevated adiposity in women aggravates polycystic ovary syndrome, ovulatory dysfunction and decreases the reproductive capacity. In obese men, fertility is diminished due to altered activity of the hypothalamo- pituitary-gonadal (HPG) axis and defective steroidogenesis in the testis. The increasing rates of childhood obesity have been correlated with early puberty and its deleterious consequences. Earlier menarche in girls is associated with increased risk of adult obesity, type 2 Diabetes and breast cancer. Thus, metabolic cues are essential signals for the onset of puberty and the adequate functioning of the reproductive system in adult life. The adipocyte hormone leptin informs the amount of energy stored to the HPG axis. Humans and mice with leptin signaling deficiency are obese and infertile, remaining in a pre-pubertal state. Although important for proof-of-principle, these mutations are rare. Human obesity is associated with hyperleptinemia, not leptin deficiency. Obese individuals exhibit low or absent response to leptin administration suggesting a functional leptin resistance, what contributes to the fertility deficits induced by excess energy stores. The recent development of molecular techniques for brain mapping and the use of genetically-modified murine models have enhanced our understanding of the brain sites involved in metabolic control. However, the neural basis for the primary reproductive actions of metabolic cues remains unclear. Our laboratory has identified the hypothalamic ventral premammillary nucleus (PMV) as an essential relay of leptin action in reproductive physiology. Guided by strong preliminary data, we hypothesize that the PMV has three distinct neuronal components (i.e., excitatory, inhibitory, and synchronizer) and that the balance among them determines the response of the HPG axis to metabolic cues. This hypothesis will be tested in three independent but complementary aims. In aims 1 and 2, we will use viro- and chemo-genetic in mouse models to determine the roles of glutamate neurotransmission (excitatory component) and dopamine transporter-expressing neurons (inhibitory component) in reproductive control. In Aim 3, we will assess the action of nitric oxide (synchronizer component) in the activity of the PMV neuronal network using mouse genetics and calcium imaging. Results from these experiments will open new opportunities for the understanding of the neural basis of the metabolic control of puberty initiation and reproductive function. Our findings will allow site-specific investigation of the causes and mechanisms underlying the reproductive deficits induced by metabolic disorders (e.g., obesity, diabetes, anorexia), including early puberty, ovulatory dysfunction, hypothalamic amenorrhea and infertility.