2026 ECNP Congress

PS04-4012

Sex-specific role of neuroplasticity factor BDNF in behavioral, neurobiological, and metabolic effects of ketogenic diet in mice

Ilya Smolensky — K. Zajak-Bakri, F. Precetti, V. Begni, R. Guzman, M.A. Riva, D. Inta · University of Fribourg, Translational Psychiatry Lab, Fribourg, Switzerland

2026 ECNP Congress

Ketogenic diet (KD) is being actively used not only for epilepsy [1] and metabolic diseases [2], but also for mental disorders such as depression, bipolar disorder, and schizophrenia [3]. Several neurobiological pathways have been suggested to mediate effect of nutrition for the brain and mental health with neuroplasticity factors among them [4]. To explore their role, we explored the effect of KD in male and female mice deficient in key neuroplasticity factor BDNF. 10 to 14-week-old WT and BDNF heterozygous mice, were kept on medium-chain fat-based KD (75% fats, 10% proteins, 3% carbohydrates) or regular diet (RD, 5% fats, 19% protein, 59% carbohydrates) during 4 weeks. Then mice underwent behavioral testing in the open field test for motor activity, social interaction test for social exploration, and tail suspension test for depression-like behavior before they were dissected for ex vivo analysis of brain and blood samples.

Neither diet nor genotype had any effect on the mouse behavior. BDNF deficiency accelerated body weight gain in both sexes (males 3.6±0.4 vs 5.2±0.9 g in five weeks; females 3.0±0.3 vs 133±9 g), while, in line with our previous report [5], KD reduced body weight gain only in males, regardless of the genotype (WT 3.6±0.4 vs 1.0±0.4; Bdnf+/- 5.2±0.9 vs 3.2±0.6). Blood analysis revealed that BHB elevation was not as strong in Bdnf+/- mice as in WT (males 1.0±0.1 mM vs 0.7±0.1 mM; females 1.8±0.2 mM vs 0.7±0.1 mM), which means that BDNF is involved in the ketogenesis. Increased TNFa level revealed a pro-inflammatory effect of the KD, in both WT (males 5±1 vs 7±1 ng/mL; females 5±1 vs 7±1 ng/mL) and BDNF mutants (males 6±1 vs 8±1 ng/mL; females 5±1 vs 8±1 ng/mL).

Metabolic hormones, insulin and leptin, were affected by the KD only in males in a genotype-specific fashion: insulin decreased only in WT (114±21 vs 40±9 ng/mL) while leptin increased only in Bdnf+/- mice (2±1 vs 14±2 mg/mL). Insulin level also correlated with a BHB level showing that lack of an effect in mutant mice resulted from a weaker BHB production.

In the brain, BDNF deficiency led to the opposite sex- and region-specific effect. Vesicular glutamate transporter VGLUT1, a marker of excitatory neurotransmission, was affected only in males: up-regulated (155% of RD expression) in WT by KD in the prefrontal cortex and by BDNF deficiency (128% of WT) in the ventral hippocampus. Vesicular GABA transporter VGAT, a marker of inhibitory neurotransmission, was down-regulated by KD in the ventral hippocampus of WT females (67% of RD) while up-regulated in Bdnf +/- males in prefrontal cortex (75% vs 117% of WT RD) and in ventral hippocampus (28% vs 72% of WT RD). Resulting VGLUT1/VGAT ration suggests that BDNF deficiency shifts neurotransmission balance towards excitation in males while towards inhibition in females. GCLC enzyme expression was up-regulated in Bdnf +/- females in both prefrontal cortex (172% of WT) and ventral hippocampus (156% of WT) suggesting enhanced antioxidant activity in mutant mice.

These data suggest a crucial role of BDNF in metabolic and neurobiological effects of ketogenic diet.

References

  1. Martin-McGill, K.J., Bresnahan, R., Levy, R.G., Cooper, P.N., 2020. Ketogenic diets for drug-resistant epilepsy. Cochrane Database of Systematic Reviews, 11.
  2. Choi, Y.J., Jeon, S.-M., Shin, S., 2020. Impact of a Ketogenic Diet on Metabolic Parameters in Patients with Obesity or Overweight and with or without Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Nutrients, 12(7).
  3. Janssen-Aguilar, R., Vije, T., Peera, M., Al-Shamali, H.F., Meshkat, S., Lin, Q, et al., 2025. Ketogenic Diets and Depression and Anxiety: A Systematic Review and Meta-Analysis. JAMA Psychiatry, 83(1).
  4. Mohamadinarab, M., Saidpour, A., Dehghani, A., Rahbarinejad, P., Ranjbar, G., Norouzy, A., et al., 2026. The effect of dietary interventions on brain-derived neurotrophic factor (BDNF) levels in adults: a systematic review of clinical trials. BMC Nutrition, 12(1).
  5. Smolensky, I., Zajac-Bakri, K., Odermatt, T.S., Brégère, C., Cryan, J.F., Guzman, R., Inta, D., 2023. Sex-specific differences in metabolic hormone and adipose tissue dynamics induced by moderate low-carbohydrate and ketogenic diet. Scientific Reports, 13.