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Li Tao/Cao Yang/Li Nanfang's latest research shows that sleep disorders can be improved by acetate regulating glucose homeostasis!

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Sleep is essential for overall health, and disrupted sleep increases the risk of metabolic, cognitive, and cardiovascular dysfunction; however, the molecular mechanisms remain poorly understood.

On August 19, 2024, Li Tao of Sichuan University, Cao Yang of University of Science and Technology of China and Li Nanfang of Xinjiang Uygur Autonomous Region People's Hospital jointly communicated inCell Metabolism（IF=27.7）Published online entitled"Acetate enables metabolic fitness and cognitive performance during sleep disruption"'s research paper,The studyFoundAcetate can promote metabolic health and cognitive performance when sleep is disrupted.

The study utilized the Chronic Sleep Fragment (SF)mouse model studyHow sleep disorders lead to metabolic imbalance and cognitive impairment. SF mice exhibit impaired cognition, glucose metabolism, and insulin sensitivity compared to controls. Elevated acetate levels in astrocytes in the hypothalamus of SF mice were found to be a defensive response. By increasing acetate levels through either acetate infusion or astrocyte-specific Acss1 deletion, the researchers observed a reduction in metabolic and cognitive impairment in the SF mice. Mechanically, acetic acid binds to and activates pyruvate carboxylase, thereby restoring glycolysis andtricarboxylic acid cycle. Among the individuals most commonly affected by SF, patients with obstructive sleep apnea exhibit elevated acetate levels when combined with type 2 diabetes.The study reveals the protective effect of acetate on sleep-induced metabolic and cognitive disorders.

Sleep is a basic physiological process that is essential for maintaining overall health, but modern lifestyle factors lead to an increase in poor sleep or insufficient sleep, which leads to various health problems. Sleep fragmentation (SF) is characterized by disturbances in sleep architecture and is prevalent in diseases such as obstructive sleep apnea (OSA), aging, and neurodegenerative diseases. Chronic sleep disruption is associated with deleterious physiological consequences, including metabolic, cognitive, cardiovascular, and immune dysfunction. For example, sleep disruption may alter brain metabolism and disrupt the regulation of metabolic hormones such as leptin and ghrelin, leading to cognitive dysfunction and the development of type 2 diabetes (T2D). In addition, chronic sleep disruption can lead to cell damage and death in various tissues, and patients with sleep apnea exhibit disruption of the intestinal barrier and intestinal microbiota.Addressing sleep disorders may be essential to prevent metabolic dysfunction, and vice versa. However, the molecular mechanisms linking sleep disruption to metabolic disorders remain poorly understood.

The brain plays a central role in regulating metabolic physiology and cognitive function. Hypothalamic paraventricular nucleus (PVN) has emerged as a key mediator of energy homeostasis astrocytes regulate whole-body glucose homeostasis in response to insulin signaling and has been implicated in obesity-induced inflammation andPVNReactive gliomas.The specific molecular mechanism of the interaction between sleep disruption, hypothalamic function and metabolic disorders is not clear.

An increasing number of studies have emphasized the role of metabolites as signaling molecules in regulating metabolic and cognitive functions.Microbial-derived metabolites, such as acetate, regulate various pathways through a two-way interaction between the brain and the gut. Acetic acid has multiple functions, including energy production, lipid synthesis, and protein acetylation.A previous clinical study found that acetate supplementation in heavy drinkers can support cerebral metabolism and may reduce withdrawal symptoms. Understanding the role of acetate in metabolic homeostasis and its underlying mechanisms is essential to elucidate the coordination of metabolism and brain function.
In this study, the researchers aimed to elucidate the molecular mechanisms underlying cognitive and metabolic regulation in a mouse model of sleep disorders. Systemic metabolic dysfunction, including impaired glucose tolerance and impaired insulin sensitivity, was initially observed in SF mice compared to control (CON) mice.Along with metabolic dysfunction, SF mice also exhibit cognitive decline, as measured by impairment in spatial learning and memory. Decreased acetate metabolism and acetate accumulation in the hypothalamus of SF mice compared to controls.Thus, an attempt was made to infuse mice with acetic acid and induce astrocyte-specific deletionAcss1to increase acetic acid levels in SF mice, thereby deciphering the functional role and underlying mechanisms of acetic acid. Then, the role of acetate in attenuating glucose metabolism and insulin signaling deficits and supplementing the hypothalamic tricarboxylic acid (TCA) cycle was evaluated. Furthermore, this protective effect of acetate is mediated by its binding to and activation of pyruvate carboxylase (PC).Taken together, the study reveals a previously unrecognized function of acetate in preventing cognitive and metabolic disorders during sleep disorders.

Professor Li Tao (Lead Contact) from West China Hospital of Sichuan University, Professor Cao Yang from the University of Science and Technology of China and Professor Li Nanfang from the People's Hospital of Xinjiang Autonomous Region are the co-authors of the paper. He Qinqin, Dr. Jian Liwei, Associate Professor Wang Yanyan and Zhang Yarong, members of Li Tao's research group, are the co-first authors of the paper.

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