Acute ketone monoester supplementation in young adults: modulating metabolic and neurocognitive functions across body weights

This study investigated the acute effects of ketone monoester on metabolic and neurocognitive indicators and underlying metabolism-brain-cognition interactions among young adults of healthy weight (HW) and those with overweight/obesity (OW). Forty participants were divided into two groups: HW (n = 20, age 23.80 ± 3.96 years, body mass index (BMI) 21.49 ± 1.80 kg/m²) and OW (n = 20, age 22.00 ± 2.13 years, BMI 28.23 ± 3.48 kg/m²). Each participant completed two trials (ketone monoester vs. placebo, 395 mg/kg dose) in a randomized order. Metabolic indicators (blood beta-hydroxybutyrate (BHB) and glucose) and neurocognitive function (causal density via functional near-infrared spectroscopy and cognitive interference via the Stroop task) were measured at baseline, 30 min, and 90 min post-supplementation. A chain mediation model was constructed to test the indirect effects of BHB level on cognitive interference through mediators like blood glucose and causal density. In the linear mixed models, significant effects were observed for trial (β =−0.92, 0.20, −0.04, 25.53) and assessment time (β = 0.50, −0.14, 0.09, −62.88) in BHB, glucose, causal density, and cognitive interference (p < 0.05), but not for group factors. Compared to OW, the effects of ketone monoester on prefrontal connectomes were more enduring in the HW (p < 0.05). Elevated BHB level improved cognitive function through decreasing glucose level and increasing causal density, with an estimate of −0.63. Acute ketone monoester supplementation elevated levels of blood BHB and prefrontal connectomes and decreased levels of glucose and cognitive interference, regardless of weight status. Elevated blood BHB enhanced cognitive function through multi-tiered neurometabolic pathways. Clinical trial registration: ClinicalTrials.gov (ID: NCT06368297).