Medium-Chain Triglyceride Administration Induces Antidepressant Effects in Animal Models by Increasing Beta-Hydroxybutyrate Levels

Abstract

Background: Inflammation is believed to contribute to the pathophysiology of depression, with increased levels of inflammatory cytokines, such as interleukin-1β (IL-1β), observed in patients. Depression is also common in individuals with chronic inflammatory diseases. IL-1β disrupts synaptic transmission and reduces neurogenesis in the hippocampus, playing a crucial role in depression development. Our prior research found that stress activates microglia in the brain to produce IL-1β via the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. Additionally, β-hydroxybutyrate (BHB), an endogenous ketone body, alleviates stress-induced depression by inhibiting NLRP3 activation and IL-1β production. However, BHB's poor bioavailability limits its effectiveness. Medium-chain triglycerides (MCTs) can increase blood BHB levels, making them a potential treatment for stress-induced depression.

Methods: We tested MCT in two animal models: social defeat (SD) in mice and chronic unpredictable stress (CUS) in rats. MCT was orally administered to both groups to assess blood BHB levels. Behavioral tests, including the forced swim test (FST), were performed, and brain tissue was analyzed for IL-1β levels and spine density.

Results: MCT administration increased blood BHB levels 7-11 times within 1 hour. In the SD model, MCT significantly reduced immobility time in the FST, suggesting antidepressant effects. While the CUS model showed no significant change, a trend toward reduced immobility time was observed. MCT treatment also reduced stress-induced IL-1β levels in the rat hippocampus, although spine density remained unchanged.

Conclusion: MCT appears to alleviate stress-induced depression-like behaviors, likely through the suppression of IL-1β in the hippocampus. Owing to its ease of oral administration, MCT may offer a practical treatment for stress-related depression.

Keywords: beta-hydroxybutyrate; depression; triglyceride.

Fig. 1.

Social defeat stress model in mice. C57BL/6J mice were placed in the living spaces of CD1 mice for 10 minutes once per day. For the remaining time each day, C57BL/6J mice lived next to the CD1 mice that attacked them. This process was repeated for 10 days, with different numbers of CD1 mice used each day. After 10 days of SD, the C57BL/6J mice underwent the forced swimming test. Four groups were established: 1) no stress control (+LCT 0.1 mL), 2) SD stress + LCT 0.1 mL, 3) SD stress + MCT 0.05 mL + LCT 0.05 mL, and 4) SD stress + MCT 0.1 mL (n = 6–7). LCT, long-chain triglyceride; MCT, medium-chain triglyceride; SD, social defeat.

Fig. 2.

Chronic stress model in rats. Sprague–Dawley rats were exposed to 12 different stressors twice daily for 5 weeks. After the stress period, the Forced Swimming Test was performed, and brain tissue was collected. The rats were divided into five groups: 1) no stress control (+ LCT 0.3 mL), 2) CUS + LCT 0.3 mL, 3) CUS + MCT 0.1 mL + LCT 0.2 mL, 4) CUS + MCT 0.2 mL + LCT 0.1 mL, and 5) CUS + MCT 0.3 mL (n = 4–5). CUS, chronic unpredictable stress; LCT, long-chain triglyceride; MCT, medium-chain triglyceride.

Fig. 3.

Golgi staining. Spine density was measured on secondary dendrites approximately 200 µm from the cell body in the CA1, DG, and PFC regions of the hippocampus. The number of spines was counted on well-defined secondary dendrites with lengths of 50–100 µm, and spine density was measured per 10 µm of dendritic length. Only spines protruding perpendicular to the dendrites were counted. For all animals, four neurons from each brain region (CA1, DG, and PFC) were selected, and the average spine density for each region was calculated. PFC, prefrontal cortex.

Fig. 4.

Blood BHB levels in mice and rats. The mice and rats were orally administered MCT and LCT, respectively. MCT administration resulted in a peak in BHB concentration at 1 hour (approximately 7–11 times the baseline), which returned to baseline after 3 hours. BHB, beta-hydroxybutyrate; LCT, long-chain triglyceride; MCT, medium-chain triglyceride.

Fig. 5.

Forced swimming test in mice. The graph shows immobility time during the 6-minute forced swimming test. SD significantly increased the immobility time compared with that in the control group, but MCT 0.1 mL significantly reduced the immobility time. MCT, medium-chain triglyceride; SD, social defeat.

Fig. 6.

Forced swimming test in rats. The graph shows the immobility time during the 6-minute forced swimming test. CUS tended to increase immobility time compared with that in the control group, but MCT 0.3 mL showed a trend of decreasing immobility time, returning to levels similar to the control group. CUS, chronic unpredictable stress; MCT, medium-chain triglyceride.

Fig. 7.

IL-1β levels in the hippocampus. Western blot analysis showing a tendency for increased IL-1β levels in the hippocampus following CUS, but MCT treatment suppressed the increase. CUS, chronic unpredictable stress; IL, interleukin; MCT, medium-chain triglyceride.

Fig. 8.

Spine counts in the hippocampus (CA1, DG) and PFC. No significant changes in spine count observed in response to CUS or MCT treatment. CUS, chronic unpredictable stress; MCT, medium-chain triglyceride.