Acetate enables metabolic fitness and cognitive performance during sleep disruption, 2024, Qinqin He et al

Highlights
Chronic SF impairs glucose metabolism and cognitive performance in mice
Hypothalamic acetate levels are adaptively elevated in response to SF
Acetate mitigates dysglycemia, cognitive impairment, and inflammation in SF mice
Acetate binds and activates PC to restore glycolysis in hypothalamic astrocytes

Summary
Sleep is essential for overall health, and its disruption is linked to increased risks of metabolic, cognitive, and cardiovascular dysfunctions; however, the molecular mechanisms remain poorly understood.

This study investigated how sleep disturbances contribute to metabolic imbalance and cognition impairment using a chronic sleep fragmentation (SF) mouse model. SF mice exhibited impaired cognition, glucose metabolism, and insulin sensitivity compared with controls.

We identified increased acetate levels in hypothalamic astrocytes as a defensive response in SF mice. Through acetate infusion or astrocyte-specific Acss1 deletion to elevate acetate levels, we observed mitigated metabolic and cognitive impairments in SF mice. Mechanistically, acetate binds and activates pyruvate carboxylase, thereby restoring glycolysis and the tricarboxylic acid cycle. Among individuals most commonly affected by SF, patients with obstructive sleep apnea exhibited elevated acetate levels when coupled with type 2 diabetes.

Our study uncovers the protective effect of acetate against sleep-induced metabolic and cognitive impairments.

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