Hepatic HMGCS2-derived β-hydroxybutyrate attenuates hippocampal insulin resistance and neuroinflammation to promote MASLD-induced cognitive function

Cognitive impairment is a known complication of metabolic dysfunction-associated steatotic liver disease (MASLD), and β-hydroxybutyrate (BHB), a ketone body providing alternative brain energy under metabolic stress, may exert neuroprotective effects. This study explored BHB's role in MASLD-related cognitive impairment and its underlying mechanisms using a 20-week high-fat diet (HFD)-induced MASLD mouse model with cognitive dysfunction, comparing 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) knockout (KO), wild-type (WT), and exogenous BHB-supplemented mice. Key outcomes included hippocampal pathology, neuroinflammation, insulin resistance, amyloid-β (Aβ) deposition, tau phosphorylation, glucose/lipid homeostasis, and cognitive function. Results showed Hmgcs2 KO mice exhibited worse metabolic dysregulation (elevated triglycerides, cholesterol, hepatic lipid accumulation, impaired glucose tolerance, increased insulin, reduced BHB), cognitive decline (confirmed by Y-maze and novel object recognition tests), hippocampal p-Tau/Aβ aggregation, neuroinflammation (elevated iNOS, COX-2, IL-1β), and impaired IRS/PI3K/AKT/GSK3β signaling, whereas exogenous BHB supplementation alleviated these phenotypes. Collectively, reduced Hmgcs2 expression and BHB levels critically contribute to MASLD-induced cognitive impairment via cerebral insulin signaling disruption and neuroinflammation, highlighting BHB's therapeutic potential.