DIFFERENTIAL EFFECTS OF SATURATED AND UNSATURATED FATS ON MOUSE BRAIN FUNCTION: A NEUROIMAGING STUDY

High-fat diet (HFD) consumption induces metabolic and cognitive alterations, yet the role of fat composition and sex in shaping brain metabolic responses remains poorly understood. Experimental evidence suggests that saturated fats are particularly detrimental to hippocampal function, but their impact on whole-brain glucose metabolism in vivo has not been systematically addressed.
In this study, we examined the long-term effects of saturated and unsaturated fat intake on brain glucose metabolism in male and female mice using 18F-FDG positron emission tomography (PET). Juvenile C57BL/6J mice of both sexes were fed for eight weeks with a standard diet (SD), a saturated oil–enriched diet (SOLF), or an unsaturated oil–enriched diet (UOLF). Brain glucose uptake was analysed using region-of-interest analysis, and voxelwise statistical parametric mapping.
SOLF induced a robust reduction in global brain glucose uptake in both sexes, affecting multiple subcortical areas, mainly in the forebrain and midbrain in males and midbrain and thalamus in females. In contrast, UOLF produced striking sex-dependent effects: female mice showed reduced glucose uptake primarily in thalamic, hippocampal and midbrain regions, whereas male mice exhibited preserved or increased metabolism in subcortical areas.
These findings demonstrate that the neural impact of HFD critically depends on fat quality and sex. While saturated fats consistently impair brain glucose metabolism, unsaturated fats exert divergent effects in males and females, suggesting sex-specific metabolic vulnerability and potential compensatory mechanisms. Our results highlight the importance of considering both dietary fat composition and biological sex when assessing the neurobiological consequences of HFD.