Elevated O-GlcNAcylation Enhances Metabolic Rate and Reduces the Excitability of Hypothalamic ARC Neurons in 10-month-old Male Mice

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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 Oga +/-mice with elevated O-GlcNAcylation levels show increased energy expenditure, but do not show significant alterations in motor function or glucose tolerance.Our ex vivo electrophysiology experiments revealed that Oga +/-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.

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