Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate

Extensive research highlights impaired brain energy metabolism in neuropsychiatric disorders, whereas much less is known about the role of peripheral metabolic state. Liver is the metabolic hub, and herein, we demonstrated that hepatic hydrolysis of acetyl-coenzyme A, a central metabolic intermediate, signals the brain and helps buffer stress. Using a chronic social defeat stress paradigm in male mice, we observed a hepatic glucose-to-acetate metabolic switch followed by a glucocorticoid-repressed transcription of the acetyl-coenzyme A hydrolase, acetyl-coenzyme A thioesterase 12, to confer stress vulnerability. Hepatic overexpression of acetyl-coenzyme A thioesterase 12 alleviated depression-like phenotypes via increasing acetate output to promote histone acetylation in the ventral hippocampus, which bolstered the expression of programmed cell death ligand 1 in astrocytes, limiting neuroinflammation and rescuing inhibitory synaptic transmission dysfunction. Our findings demonstrate hepatic acetyl-coenzyme A hydrolysis serves as a key liver-brain axis component that regulates depression susceptibility. Overall design: We used RNA sequencing to analyze differentially expressed genes in the vHip of control mice, CSDS-exposed, AAV8-eGFP mice exposed to SSDS and hepatic ACOT12 gene knockdown mice exposed to SSDS.