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High-Fat Diet Alters Behavior and Hippocampal Gene Expression.
Melissa S Totten1, Ava L Peterson1, Derek M Pierce2
1Chemistry, Biochemistry, and Nutrition Program, Salem College, Winston-Salem, NC 27101, USA.
International Journal of Molecular Sciences
|September 27, 2025
Summary
High-fat diets alter behavior and brain gene expression, with male mice of specific strains showing the greatest impact. Sex and genetics significantly influence diet-related changes in the brain.
Area of Science:
- Neuroscience
- Dietary Science
- Genetics
Background:
- High-fat diets (HFD) are associated with altered gene expression and behavioral changes.
- Understanding the influence of sex and genetic background is crucial for diet-related health outcomes.
Purpose of the Study:
- To investigate the effects of a HFD on behavior and hippocampal gene expression.
- To evaluate sex and genetic differences in response to HFD in mice.
Main Methods:
- Male and female C57BL/6J (B6J) and DBA/2J (D2J) mice were fed a control or HFD for 16 weeks.
- Behavioral tests included open field, nestlet shredding, and novel object recognition.
- mRNA expression of alpha synuclein (αSYN), amyloid precursor protein (APP), and brain-derived neurotrophic factor (BDNF) was measured.
Main Results:
- HFD reduced nestlet shredding in male B6J mice and increased fecal boli in HFD male B6Js.
- No significant memory differences were observed.
- Significant diet-sex-strain interactions for αSYN and APP mRNA; HFD upregulated αSYN (7-fold) and APP (10-fold) in male B6J hippocampi.
- BDNF expression showed strain-sex interactions but no diet effect.
Conclusions:
- HFD significantly impacts male B6J mice's behavior and hippocampal gene expression.
- Biological sex and genetic background are critical factors in diet-induced brain changes.
- Dietary interventions should consider individual genetic and sex-specific responses.

