High-fat diet differentially alters hippocampal lipidomic and metabolomic profiles and cognition-related behavior in wild-type and LDL receptor-deficient mice.

Obesity and dyslipidemia are linked to cognitive decline, yet the role of LDL receptor (LDLr) deficiency in cognitive susceptibility to high-fat diet (HFD) remains unclear. This study examined the effects of HFD on cognitive function and hippocampal lipidomic and metabolomic profiles in wild-type (WT) and LDLr⁻/⁻ mice. Male mice of both genotypes were fed a control diet or HFD for 12 weeks and assessed for body weight, serum lipid profiles, anxiety-like behavior, spatial and recognition memory, and hippocampal lipidomic/metabolomic alterations using untargeted LC-MS/MS. HFD increased body weight and aggravated circulating lipid abnormalities, most prominently in LDLr⁻/⁻ mice. LDLr deficiency was associated with anxiety-like behavior and impairments in spatial and recognition memory, whereas HFD impaired recognition memory in WT mice but did not further worsen most behavioral outcomes in LDLr⁻/⁻ mice. Hippocampal lipidomics revealed genotype- and diet-dependent remodeling of sphingolipid and glycerophospholipid metabolism, with prominent changes in phosphatidylinositol, sterol lipid, phosphatidylethanolamine-related lipids, and phosphatidylethanol. Metabolomics indicated that LDLr deficiency was a major contributor to hippocampal metabolic reprogramming involving SLC-mediated transport and alanine/aspartate/glutamate metabolism, with additional HFD-associated alterations in glutamate-related pathways and oxidative phosphorylation. Integrated analysis linked energy-related metabolites with phospholipid remodeling and nucleotide sugar derivatives with sphingomyelins. These findings suggest that LDLr deficiency establishes a hippocampal lipid-metabolic vulnerability associated with cognitive impairment, while HFD primarily intensifies systemic dyslipidemia and hippocampal molecular remodeling.