To prevent getting lost, the elevator goes directly to the safety island to report Liu Yadong A
Source: Metz Medical Author: Swagpp
Sleep fragmentation (SF) refers to sleep disruption and wakefulness due to various reasons during sleep, which can be simply understood as "frequent awakenings at night".
As an intuitive example, if you are going to travel or participate in a big event the next day, many people are easily "so excited that they can't sleep" the night before, and wake up to see how it is only 1 o'clock/3 o'clock/5 o'clock...... Of course, certain special populations, such as parents of newborns or migrant workers on night shifts, are more likely to have long-term fragmented sleep. The so-called "don't sleep at night, collapse during the day", don't take sleep fragmentation seriously! It seems that sleeping at 11 o'clock at night and waking up at 7 o'clock in the morning has experienced the "optimal sleep duration" of 7-8 hours, but the daytime productivity of such people is even worse than that of only sleeping 4 hours a night. A large number of studies have confirmed that sleep fragmentation will lead to a lack of continuous and stable sleep in the body, and short-term SF will cause symptoms such as drowsiness, memory loss, and difficulty concentrating during the day. If it develops into a long-term period, chronic sleep disruption can further induce a "collapse" of metabolic, cognitive, cardiovascular, and immune systems. In order to more clearly observe the relationship between SF and metabolic disorders, a research team from West China Hospital of Sichuan University constructed a mouse model of chronic sleep fragmentation (SF). It was found that compared with the control group, the cognitive ability, glucose metabolism and insulin sensitivity of the SF mice were impaired. However, there is also a turnaround! The key to reversing this metabolic imbalance and cognitive dysfunction is acetic acid. Specifically, by injecting acetate or knocking out astrocyte-specific Acss1 to increase acetic acid levels, the researchers observed remission of metabolic and cognitive impairment in SF mice. This study is the first to clarify the protective role of acetic acid in sleep disorders, and may provide a treatment for patients with sleep disorders in the future.
doi: 10.1016/j.cmet.2024.07.019To mimic the sleep patterns of patients with SF, the researchers used an electromechanical cleaner to administer tactile stimulation every 2 minutes to "wake up" sleeping mice, equivalent to patients with severe obstructive sleep apnea syndrome (an average of 30 wake-ups per hour). After 14 days of SF, the experimental group of mice exhibited a characteristic fragment sleep pattern. The results showed that after a long period of SF, the glucose metabolism and cognitive ability of mice were severely impaired. Specifically, the SF group experienced significant blood glucose abnormalities, including elevated plasma glucose levels, glucose intolerance, and insulin resistance, compared to the control group. Further plasma proteome analysis observed 65 up-regulated and 35 down-regulated, and these proteins were mainly related to glucose homeostasis, which once again confirmed that SF disrupts glucose metabolism in mice. Not only that, but SF mice also showed impaired cognitive performance, as evidenced by a reduction in travel distance, reduced time spent, fewer crossings of the target quadrant, and a significant decrease in the ability to recognize new objects in the Morris water maze test.
Considering that the brain plays a crucial role in regulating metabolic physiology and cognitive function, researchers have focused more on the brain. Assessment of glucose uptake in the brain revealed a significant decrease in fluorodeoxyglucose (18F-FDG) uptake in the hypothalamus of mice in the SF group, as well as a downward trend in the hippocampus or cortex. In addition, there is a decrease in the appearance of glucose involved in glycolysis and TCA circulation in the brain. That is, SF also reduced glucose metabolism in the brain regions involved.
SF mice exhibit decreased glucose metabolism and cognitive impairment
Further metabolomic analysis yielded interesting results, as the researchers observed that 39 metabolites were upregulated and 7 downregulated in the plasma of the SF group of mice. Among them, the levels of short-chain fatty acids (SCFAs) have increased significantly, including the common acetic acid, propionic acid and butyric acid. Among these differentially regulated levels of metabolites, acetate "stands out", i.e., the concentration of acetate in the plasma of SF mice is significantly higher than that of the control group. So, the researchers set their sights on acetate. In fact, acetate increased in the blood circulation and hypothalamus of mice in the SF group, more closely resembling an "adaptive" elevation. If acetate (1.0 mg/g orally daily) is administered at this time, a range of negative effects of SF can be reversed, including improved glucose metabolism and cognitive dysfunction. Of course, there is another reliable way to do this: knocking out the ACSS1 gene. ACSS1 converts acetic acid into acetyl-CoA in the mitochondria, and if you want to have more acetic acid content in the body, you can also start from this link, by knocking out ACSS1 can block the conversion of acetic acid, so that more acetate actuates in the brain. The researchers observed in mice with astrocyte-specific Acss1 gene knockout that Acss1 cKO reversed metabolic defects in SF mice, including improved glucose tolerance, insulin sensitivity, and reduced insulin resistance index. Consistent with improved glycemic control, cKO mice also experienced improved cognitive performance, as evidenced by increased distance and time traveled in the target quadrant and enhanced ability to recognize new objects.
Intragastric acetate improved glycemic control, insulin sensitivity, and cognitive performance in the SF group
Mechanistically, acetic acid exerts a protective effect because it binds to and activates pyruvate carboxylase (PC). PC is a key enzyme involved in glucose metabolism in hypothalamic astrocytes, which explains why acetic acid activates acetic acid to restore glycolysis and the tricarboxylic acid cycle (TCA), further regulating glucose homeostasis and cognitive performance. Last but not least, can acetate treat SF-induced impaired glucose metabolism? Can you push mice and humans? The researchers first performed the validation in SF mice. After 14 consecutive days of acetate administration, the glucose homeostasis and cognitive abilities of SF mice were significantly improved. In other words, experiments in mice have shown that acetate can be used to treat sleep-wake disorders associated with metabolic and cognitive disorders. Next, it's up to the human experiment! The investigators studied patients with obstructive sleep apnea (OSA), a subset of people who typically develop SF symptoms. Finally, 25 patients with OSA alone, 25 patients with OSA and type 2 diabetes mellitus (T2D), and 25 control groups were recruited to carry out plasma-targeted SCFAs metabolomics studies. The results are highly consistent with previous animal studies. Compared with the control group, the plasma acetate levels in patients with OSA and T2D were significantly higher, but the levels of other SCFAs remained unchanged, once again confirming the correlation between acetate and glucose homeostasis. In addition, genetic association analysis based on a large human sample further identified the Acss1 variant, and found that Acss1 is not only related to sleep, but also closely related to glucose homeostasis. This means that in people with sleep disorders and impaired glucose metabolism, regulating Acss1-supported acetate metabolism may be effective in alleviating disease conditions.
In summary, sleep fragmentation can induce neurological and cardiovascular disorders, including cognitive dysfunction, metabolic disorders, and diabetes. However, acetate injections can alleviate and reverse this phenomenon, or provide new ideas for the treatment of sleep disorders.
The researchers concluded that in order to improve sleep quality or cognitive and metabolic health of diabetic patients, it is recommended to consume more foods rich in acetate fiber (such as whole grains, vegetables, fruits, bacteria and algae), direct oral acetate (such as vinegar), or probiotic supplementation. If you usually have a fragmented sleep, you might as well try the above small methods to see if it works~
Resources:
[1] He Q, Ji L, Wang Y, Zhang Y, Wang H, Wang J, Zhu Q, Xie M, Ou W, Liu J, Tang K, Lu K, Liu Q, Zhou J, Zhao R, Cai X, Li N, Cao Y, Li T. Acetate enables metabolic fitness and cognitive performance during sleep disruption. Cell Metab. 2024 Sep 3; 36(9):1998-2014.e15. doi: 10.1016/j.cmet.2024.07.019. Epub 2024 Aug 19. PMID: 39163862