Acetate ameliorates glucolipid metabolic dysregulation and neuroinflammation in diabetic cognitive impairment via enhanced mitophagy.

BACKGROUND

Diabetic cognitive impairment (DCI) is an increasingly recognized complication of type 2 diabetes mellitus (T2DM) with limited effective therapies. Short-chain fatty acids (SCFAs) have been implicated in metabolic regulation and neuronal health, yet comparisons of acetate, propionate, butyrate, and their mixture are limited, and the mechanisms underlying neuroprotection in DCI remain insufficiently clarified.

METHODS

Ninety participants (healthy controls, T2DM, and DCI groups) were assessed for serum SCFA levels and cognitive performance using the Montreal Cognitive Assessment (MoCA). In parallel, a DCI mouse model established by a 24-week high-fat diet received 8-week supplementation with acetate, propionate, butyrate, or a mixture of the three. Glucolipid metabolism, spatial learning and memory, hippocampal neuronal damage, neuroinflammation, and mitophagy were evaluated. Based on consistency across the clinical and animal datasets, acetate was selected for mitophagy-focused mechanistic experiments, and pathway dependence was examined by co-administration of the autophagy inhibitor 3-methyladenine (3-MA).

RESULTS

Clinically, serum acetate, propionate, and butyrate were lower in T2DM and DCI than in healthy controls; only acetate showed a further significant reduction in DCI compared with T2DM. All three SCFAs were positively associated with MoCA score and inversely associated with fasting blood glucose, whereas acetate additionally showed inverse associations with lipid parameters. In mice, SCFA supplementation alleviated metabolic dysfunction, spatial learning and memory, neuronal loss, and neuroinflammation, with acetate generally producing more consistent and numerically greater improvements across these endpoints. Mechanistically, acetate enhanced hippocampal mitophagy by restoring LC3-TOMM20 colocalization and activating the PINK1/Parkin pathway. Importantly, 3-MA partially attenuated these benefits, indicating a mitophagy-dependent mechanism.

CONCLUSIONS

These integrated clinical and experimental data support a "SCFAs-mitophagy-neuroinflammation" axis linking systemic metabolism to neuronal vulnerability in DCI, and identify acetate as a promising SCFA that may enhance neuronal resilience through mitophagy activation.