Decreased β‐hydroxybutyrate and ketogenic amino acid levels in depressed human adults

β-hydroxybutyrate (BHB) is a major ketone body synthesized mainly in the liver mitochondria and is associated with stress and severity of depression in humans. It is known to alleviate depressive-like behaviors in mouse models of depression. In this study, plasma BHB, ketogenic and glucogenic amino acids selected from the Tohoku Medical Megabank Project Community-Based Cohort Study were analysed and measured using nuclear magnetic resonance spectroscopy. The Center for Epidemiologic Studies Depression Scale (CES-D) was utilized to select adult participants with depressive symptoms (CES-D ≥ 16; n = 5722) and control participants (CES-D < 16; n = 18,150). We observed significantly reduced plasma BHB, leucine, and tryptophan levels in participants with depressive symptoms. Using social defeat stress (SDS) mice models, we found that BHB levels in mice sera increased after acute SDS, but showed no change after chronic SDS, which differed from human plasma results. Furthermore, acute SDS increased mitochondrial BHB levels in the prefrontal cortex at 6 h. In contrast, chronic SDS significantly increased the amount of food intake but reduced hepatic mitochondrial BHB levels in mice. Moreover, gene transcriptions of voltage-dependent anion-selective channel 1 (Vdac1) and monocarboxylic acid transporter 1 (Mct1), major molecules relevant to mitochondrial biogenesis and BHB transporter, significantly decreased in the liver and PFC after chronic SDS exposure. These results provide evidence that hepatic and prefrontal mitochondrial biogenesis plays an important role in BHB synthesis under chronic stress and in humans with depressive symptoms.