Impact of early overnutrition on leptin signaling in hypothalamic neuropeptide Y neurons

在美国，几乎一半的儿童超重，很可能成为肥胖的成年人，患有2型糖尿病、中风、心血管疾病和过早死亡的几率增加。不幸的是，可用的非侵入性干预措施很少。肥胖对大脑和外周有相应的影响，包括对几乎所有细胞和器官系统都存在的依赖时间的过程的影响。我们知识中的一个主要缺口是早期营养过剩如何影响调节能量平衡的神经回路，特别是在功能细胞生理学水平上。我们的项目旨在使用神经生理学方法的综合组合来研究这些影响。下丘脑弓状核(ARH)对于食物摄取和代谢的动态平衡控制至关重要，它也显示出一天中基因表达的动态变化。ARH神经肽Y(NPY)“饥饿”神经元对代谢功能是必不可少的，但慢性出生后营养过剩(CPO)是如何影响这一关键细胞群的尚不清楚。目的1研究CPO对ARH-NPY神经元生理的影响。这将包括脑片电生理学，以了解一天中的时间如何影响这些神经元的神经生理学及其突触输入。瘦素是维持能量平衡的关键激素，而CPO在行为水平上诱导瘦素抵抗。此外，饮食诱导的肥胖改变了包括瘦素在内的内分泌信号的每日波动。CPO如何影响ARH-NPY神经元对瘦素的反应尚不清楚。我们将在目标2中使用电生理学方法来确定CPO改变ARH-NPY神经元中瘦素信号的机制(S)，并特别关注一天中的不同时间。有强有力的基础证据支持ARH-NPY神经元和瘦素信号对这些神经元的研究。这些实验的成功完成将大大有助于我们从功能和机制上了解早期代谢挑战对大脑的影响，并为应对儿童肥胖的长期后果提供新的途径(包括在时间领域)。

Almost half the children in the U.S. are overweight and are likely to become obese adults, suffer from increased rates of type 2 diabetes, stroke, cardiovascular disease, and premature death. Unfortunately, there are very few non-invasive interventions available. Obesity has consequential effects in the brain and periphery, including on time-of-day dependent processes, which are present in nearly all cells and organ systems. A major gap in our knowledge is how early life overnutrition impacts neural circuits that regulate energy balance, particularly at the level of function cell physiology. Our project aims to investigate these effects using an integrated combination of neurophysiological approaches. The arcuate nucleus of the hypothalamus (ARH) is critical for the homeostatic control of food intake and metabolism, that also shows dynamic changes in gene expression over the day. ARH neuropeptide Y (NPY) "hunger" neurons are essential for metabolic function, but it is unknown how chronic postnatal overnutrition (CPO) impacts this critical population of cells. Aim 1 will investigate how CPO affects the physiology of ARH-NPY neurons. This will include brain slice electrophysiology to understand how time-of-day impacts the neurophysiology of these neurons and their synaptic inputs. The hormone leptin is essential for energy balance and CPO induces leptin resistance at the behavior level. In addition, diet-induced obesity alters diurnal fluctuations in endocrine signaling, including leptin. How CPO impacts the response of ARH-NPY neurons to leptin is unknown. We will employ electrophysiological approaches in Aim 2 to determine the mechanism(s) by which CPO alters leptin signaling in ARH-NPY neurons, with particular attention to time of day. There is robust foundational evidence supporting the investigation of both ARH-NPY neurons and leptin signaling to these neurons. Successful completion of these experiments will significantly contribute to our functional and mechanistic understanding of the impacts early life metabolic challenges have on the brain, and provide new avenues (including on the temporal domain) to confront long-term outcomes of childhood obesity.