Hypothalamic leptin and insulin signals aligning metabolic state and fertility

美国儿童和青少年肥胖症的急剧增加对健康造成了严重后果。 下一代的健康。沿着其众所周知的健康风险，儿童肥胖损害 生殖健康和发展。事实上，女孩肥胖的早期发病，特别是在青春期， 促进月经不调、慢性不排卵、不孕和成年后多囊卵巢综合征的发展。 虽然这种关系的主要原因还不确定，但对胰岛素和瘦素的中枢抵抗，循环 肥胖的标志物，似乎抑制了生殖轴。主要的沟通地点 然而，代谢和生殖系统仍不清楚。 这项建议旨在推进我们的长期目标，阐明分子和遗传 代谢性不育的决定因素。我们假设瘦素和胰岛素直接作用于下丘脑 POMC和NPY/AgRP神经元向GnRH神经元提供输入。这一假设基于以下发现， POMC和NPY/AgRP神经元对瘦素和胰岛素反应的活性改变似乎取决于 磷脂酰肌醇3-激酶（PI 3 K）细胞内信号通路。此外，先前的研究表明， 大脑特异性瘦素受体和胰岛素受体敲除对生殖系统有显著影响， 轴，但通过非PI 3 K途径阻止瘦素受体信号传导并不损害生育力。所以我们 研究将确定胰岛素和瘦素通过PI 3 K信号传导是否是正常能量所必需的 稳态和（2）生殖功能和POMC神经元和/或NPY/AgRP神经元。 为了实现这些目标，我们将使用cre/lox系统遗传靶向关键神经元。 具体来说，我们将研究缺乏胰岛素和瘦素的小鼠的代谢和生殖表型 受体或功能性PI 3 K仅在POMC神经元和仅在NPY/AgRP神经元中表达。然后我们将使用 电生理学和体外可视化Akt信号传导的新方法，以确定PI 3 K缺失对神经元功能的影响。总的来说，这些数据可能为治疗和预防肥胖相关不孕症的治疗进展提供新的靶点。 希尔博士拥有生殖和代谢等不同领域的背景，是唯一有资格进行这些研究的人。在她的博士后研究期间组装的新的遗传方法将是调查相互作用的下丘脑代谢和生殖途径的未充分研究领域的有力工具。通过为她向研究独立过渡提供一个工具，该提案为专注于生殖健康的研究计划奠定了基础，并发现了治疗营养和肥胖相关不孕症的新方法。

The dramatic increases in childhood and adolescent obesity in the U.S. have serious consequences for the health of the next generation. Along with its well-known health risks, childhood obesity impairs reproductive health and development. Indeed, early onset of obesity in girls, particularly during adolescence, favors the development of menses irregularities, chronic anovulation, infertility, and PCOS in adulthood. While the primary cause of this relationship is uncertain, central resistance to insulin and leptin, circulating markers of adiposity, appears to inhibit the reproductive axis. The key sites of communication between the metabolic and reproductive systems, however, remain unclear. This proposal is designed to advance our long-term goal of elucidating the molecular and genetic determinants of metabolic infertility. We hypothesize that leptin and insulin act directly on hypothalamic POMC and NPY/AgRP neurons that provide input to GnRH neurons. This hypothesis rests on findings that altered activity of POMC and NPY/AgRP neurons in response to leptin and insulin appear to depend on the phosphatidylinositol 3-kinase (PI3K) intracellular signaling pathway. In addition, previous studies have shown that brain-specific leptin receptor and insulin receptor knockouts have dramatic effects on the reproductive axis, but preventing leptin receptor signaling through non-PI3K pathways does not impair fertility. Thus, our studies will determine if insulin and leptin signaling through PI3K is required for normal (1) energy homeostasis and (2) reproductive functioning and in POMC neurons and/or in NPY/AgRP neurons. To accomplish these goals, we will genetically target the critical neurons using the cre/lox system. Specifically, we will examine the metabolic and reproductive phenotype of mice lacking insulin and leptin receptors or functional PI3K only in POMC neurons and only in NPY/AgRP neurons. We will then use electrophysiology and a novel method of visualizing Akt signaling in vitro to determine the impact of PI3K deletion on neuronal function. Collectively, these data may provide a new target for therapeutic advances in the treatment and prevention of obesity-related infertility. With a background in the diverse fields of reproduction and metabolism, Dr. Hill is uniquely qualified to undertake these studies. The novel genetic approaches assembled during her post-doctoral fellowship will be powerful tools for investigating the understudied area of interacting hypothalamic metabolic and reproductive pathways. By providing a vehicle for her transition to research independence, this proposal lays the groundwork for a research program focused on reproductive health and the discovery of new approaches for treating nutritional and obesity-related infertility.