Integrated metabolomics and proteomics analysis reveals energy metabolism disorders in the livers of sleep-deprived mice

Abstract

Sleep deprivation (SD) has been linked to impaired mental and physical health, obesity, and various diseases. However, the molecular mechanism underlying the effects of SD in the liver is still unclear. To investigate the metabolome and proteome alterations in the liver, an in vivo model of SD was established based on automated random motion platform techniques by applying a strategy of 10 consecutive days of 20 h of sleep deprivation +4 h of resting. The liver's altered metabolites and proteins were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and data analyses were performed with MetaboAnalyst 5.0. This study found 15 differential metabolites, including 12 upregulated- metabolites and 3 downregulated- metabolites. A total of 493 proteins were differentially regulated, including 377 upregulated- proteins and 116 downregulated- proteins. The glutathione metabolism, fructose and mannose metabolism, and pyruvate metabolism pathways had significant effects on the sleep-deprived mouse livers. These three active pathways cause energy metabolism disorder and may induce obesity. In conclusion, this study demonstrates that SD could change the metabolism of glucose, and specific fatty acids, amino acids, and critical enzymes in the liver, providing a reference for the health effects of insufficient sleep. SIGNIFICANCE STATEMENT: So far, little is known about the changes in metabolites and proteins in the liver of individuals who suffer from SD. Metabolites and proteins in serum, urine and hypothalamus do not entirely reflect the effects of sleep deprivation on the whole body. In addition, many SD-induced models used the multiplatform water environment method, which causes mice to fall into the water frequently. Under this condition, the physical exertion of mice is extremely high, and it is not suitable for long-term sleep deprivation. The SD induction process has caused some influence on the model. Finally, few studies have elucidated the imbalance of energy metabolism caused by SD to induce obesity from the molecular mechanism. This study used a rotary table deprivation apparatus to trigger SD. This method will not cause excessive consumption and stimulation of mice. Furthermore, this study analyzed the metabolic and proteomic changes in the liver and enriched the range and means of metabolic and proteomic changes in sleep deprived mice. Finally, this research provides reference for elucidating the molecular mechanism of sleep deprivation causing energy metabolism disorders in the liver of mice.

Keywords: Energy metabolism; LC-MS/MS; Liver; Pathway; Sleep deprivation.