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

早期营养过剩对下丘脑神经肽 Y 神经元瘦素信号传导的影响

• 批准号: 11011729
• 负责人: Brandon L Roberts
• 金额: $ 16.82万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-01-16 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/11011729
• 关键词: Impact; early; overnutrition; leptin; signaling; Impact; early; overnutrition; leptin; signaling

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.

美国几乎一半的儿童超重，可能会成为肥胖的成年人，患有2型糖尿病，中风，心血管疾病和过早死亡的率提高。不幸的是，很少有非侵入性干预措施可用。肥胖在大脑和周围具有结果作用，包括在几乎所有细胞和器官系统中都存在的依赖时间的过程。我们知识上的一个主要差距是早期生命营养不良如何影响调节能量平衡的神经回路，尤其是在功能细胞生理水平上。我们的项目旨在通过神经生理方法的综合组合研究这些效果。下丘脑（ARH）的弧形核对于食物摄入和代谢的体内控制至关重要，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”神经元对于代谢功能至关重要，但是尚不清楚慢性产后营养（CPO）如何影响这种关键的细胞群体。 AIM 1将研究CPO如何影响ARH-NPY神经元的生理。这将包括大脑切片电生理学，以了解这些神经元及其突触输入的神经生理学的时间如何影响。激素瘦素对于能量平衡至关重要，CPO在行为水平上诱导瘦素耐药性。此外，饮食诱导的肥胖症会改变包括瘦素在内的内分泌信号传导中的昼夜波动。 CPO如何影响ARH-NPY神经元对瘦素的反应是未知的。我们将在AIM 2中采用电生理方法来确定CPO在ARH-NPY神经元中改变瘦素信号传导的机制，并特别注意一天中的时间。有强大的基础证据支持对这些神经元的ARH-NPY神经元和瘦素信号的研究。这些实验的成功完成将极大地有助于我们对早期生活代谢挑战对大脑的影响的功能和机械理解，并提供新的途径（包括在时间领域），以面对儿童肥胖的长期结局。