Succinate Modulation as a Biochemical Correlate of Metabolic and Neurobehavioral Changes Associated With Intermittent Fasting in Obesity

Aim: Obesity significantly impacts the central nervous system (CNS), increasing the risks of neuropsychiatric disorders and dementia. Intermittent fasting (IF) shows promise for improving peripheral and CNS health, but its mechanisms are unclear. Methods: Using a diet-induced obesity mouse model [10 weeks high fat diet (HFD), then 4 weeks intervention], we compared HFD, HFD-IF, ad libitum control chow (CC), and CC-IF groups. Results: Switching to CC or IF reduced body weight, fat mass, and improved glucose tolerance. Notably, CC-IF uniquely enhanced exploration and reduced anxiety-like behavior. Transcriptomics revealed HFD-induced hippocampal neuroinflammation, whereas metabolomics identified a specific succinate signature in CC-IF mice: plasma concentration decreased, whereas liver and brown adipose tissue (BAT) levels increased. Succinate supplementation mimicked CC-IF metabolic and behavioral benefits and reduced hippocampal inflammation. Conclusion: These findings suggest that regulating plasma succinate and its metabolism in liver and BAT may represent a novel biochemical correlate underlying the metabolic, neuroinflammatory, and behavioral improvements induced by IF.