Spatio-temporal analysis deciphers the energy metabolism disorders in depression based on stable isotope-resolved metabolomics.

The significant impact of depression on human life has attracted great attention. However, the unclear and highly complex pathogenesis of depression has resulted in the limited efficacy of currently available antidepressants. Therefore, it is imperative to explore the pathogenesis of depression from novel perspectives and develop next-generation antidepressants that target innovative mechanisms. In this study, the stable isotope tracing technology and a pseudo-first-order kinetics mathematical model were employed to assess the metabolic rates and the isotope distribution across various tissues from a spatio-temporal perspective. Our findings revealed that chronic unpredictable mild stress (CUMS) rats exhibited impaired tricarboxylic acid (TCA) cycle activity and activated gluconeogenesis, whereas nephrotic syndrome (NS) rats demonstrated impaired TCA cycle activity and enhanced fatty acid β-oxidation. Furthermore, our results revealed an interesting phenomenon that caecum displayed the lowest abundances in all metabolic pathways, while serum, heart, brain, and kidney displayed the highest abundances in glycolysis/gluconeogenesis, TCA cycle, neurotransmitters metabolism, and fatty acids metabolism, respectively. The results comprehensively and accurately revealed the specific pathway of energy metabolism disorders in depression from a spatio-temporal perspective. Our study provided a novel insight for exploring the pathological mechanisms of depression, identifying new therapeutic targets, and developing ideal antidepressants.