Yasmin Tamanna, Lee Yuna, Hwang Hongik, Seo Jiyeon, Kim Min Soo, Park Mikyoung, Oh Soo-Jin, Nam Min-Ho, Rhim Hyewhon
Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea.
Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Seoul 02792, Korea.
Exp Neurobiol. 2025 Aug 31;34(4):147-155. doi: 10.5607/en25012.
Aging correlates with alterations in metabolism and neuronal function, which affect the overall regulation of energy homeostasis. Recent studies have highlighted that protein O-GlcNAcylation, a common post-translational modification regulating metabolic function, is linked to aging. In particular, elevated O-GlcNAcylation increases energy expenditure, potentially due to alterations in the neuronal function of the hypothalamic arcuate nucleus (ARC), a key brain region for energy balance and metabolic processes. However, its impact on metabolism and hypothalamic neuronal activity in aged mice remains unknown. This study investigates the effect of elevated O-GlcNAcylation on metabolic rate, motor behaviors, glucose tolerance, and neuronal excitability within the hypothalamic ARC in 10-month-old mice. We demonstrate that mice with elevated O-GlcNAcylation levels show increased energy expenditure, but do not show significant alterations in motor function or glucose tolerance. Our electrophysiology experiments revealed that mice exhibited a reduced firing rate of hypothalamic ARC neurons, suggesting that the increased metabolism in these mice could be attributed to the reduced activity of ARC neurons. These findings indicate that O-GlcNAcylation plays a crucial role in maintaining metabolic balance and neuronal function in the aging brain.
衰老与新陈代谢和神经元功能的改变相关，这些改变会影响能量稳态的整体调节。最近的研究强调，蛋白质O-连接的N-乙酰葡糖胺化（一种调节代谢功能的常见翻译后修饰）与衰老有关。特别是，O-连接的N-乙酰葡糖胺化水平升高会增加能量消耗，这可能是由于下丘脑弓状核（ARC）的神经元功能发生改变所致，ARC是能量平衡和代谢过程的关键脑区。然而，其对老年小鼠新陈代谢和下丘脑神经元活动的影响仍不清楚。本研究调查了10月龄小鼠中O-连接的N-乙酰葡糖胺化水平升高对代谢率、运动行为、葡萄糖耐量以及下丘脑ARC内神经元兴奋性的影响。我们证明，O-连接的N-乙酰葡糖胺化水平升高的小鼠能量消耗增加，但运动功能或葡萄糖耐量未出现显著改变。我们的电生理实验表明，这些小鼠下丘脑ARC神经元的放电频率降低，这表明这些小鼠新陈代谢增加可能归因于ARC神经元活性降低。这些发现表明，O-连接的N-乙酰葡糖胺化在维持衰老大脑的代谢平衡和神经元功能方面起着关键作用。
