Excessive sugar consumption promotes obesity, insulin resistance, and cognitive decline—key features of metabolic dysfunction–associated brain impairment. Hippocampal insulin signaling defects, synaptic deterioration, and mitochondrial inefficiency are major contributors. β-Hydroxybutyrate (BHB), an endogenous ketone body and alternative energy substrate, exhibits neuroprotective potential in various disease models; however, its efficacy in diet-induced cognitive deficits is less defined. This study aimed to determine whether oral BHB supplementation could counteract high-sucrose-induced hippocampal and cognitive impairments in Wistar rats.

Thirty male Wistar rats (8 weeks old) were randomly assigned to three groups (n = 10 each): control (standard diet), high-sucrose diet (65 g/L sucrose in drinking water), and high-sucrose + BHB (2 g/kg/day, oral gavage) for 12 weeks. Body weight, fasting glucose, and insulin were monitored bi-weekly; insulin resistance was estimated using HOMA-IR. Cognitive performance was assessed through the Morris Water Maze, Y-Maze, and Novel Object Recognition tests. Hippocampal tissue was analyzed for synaptic proteins (PSD-95, synaptophysin), BDNF levels, and insulin receptor substrate-1 (IRS-1) phosphorylation. AMPK activation, lactate dehydrogenase activity, and mitochondrial respiration (high-resolution respirometry) were evaluated. Inflammatory cytokines (IL-6, TNF-α) were quantified by ELISA. Statistical comparisons were performed using ANOVA followed by Tukey’s post hoc test.

High-sucrose feeding increased body weight by ~30% and HOMA-IR by 45% (p < 0.01), accompanied by spatial and recognition memory deficits (escape latency ↑ 35%, p < 0.05). BHB supplementation normalized metabolic indices and restored cognitive performance to control levels. Synaptic markers (PSD-95 ↑ 40%, BDNF ↑ 35%) and mitochondrial oxygen consumption (↑ 25%) were significantly improved, while IRS-1 phosphorylation and AMPK activation returned to physiological levels. Inflammatory cytokines (IL-6, TNF-α) were reduced by ~40%, and hippocampal lactate accumulation declined by 20%.

Oral β-hydroxybutyrate supplementation effectively reverses sucrose-induced cognitive and metabolic impairments by enhancing hippocampal synaptic integrity, mitochondrial bioenergetics, and insulin sensitivity while attenuating neuroinflammation. BHB represents a promising nutritional strategy for preventing or managing diet-related cognitive dysfunction and metabolic brain disorders.