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

在美国，几乎有一半的儿童超重，并且很可能成为肥胖的成年人，患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。肥胖会对大脑和外围系统产生相应的影响，包括几乎存在于所有细胞和器官系统中的时间依赖性过程。我们对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，这是我们知识的一个主要空白。我们的项目旨在利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）对食物摄入和代谢的稳态控制至关重要，这也显示了一天中基因表达的动态变化。ARH神经肽Y （NPY）“饥饿”神经元对代谢功能至关重要，但目前尚不清楚慢性产后营养过剩（CPO）如何影响这一关键细胞群。目的1将研究CPO如何影响ARH-NPY神经元的生理。这将包括脑切片电生理学，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。激素瘦素对能量平衡至关重要，而CPO在行为水平上诱导瘦素抵抗。此外，饮食引起的肥胖会改变内分泌信号的昼夜波动，包括瘦素。CPO如何影响ARH-NPY神经元对瘦素的反应尚不清楚。在Aim 2中，我们将采用电生理方法来确定CPO改变ARH-NPY神经元中瘦素信号的机制，并特别注意一天中的时间。有强有力的基础证据支持对ARH-NPY神经元和瘦素信号传导到这些神经元的研究。这些实验的成功完成将大大有助于我们对早期生活代谢挑战对大脑影响的功能和机制的理解，并为应对儿童肥胖的长期后果提供新的途径（包括颞域）。

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.