The Effect of Exogenous Ketone Monoester Ingestion on Plasma BDNF during an Oral Glucose Tolerance Test

Brain‐derived neurotrophic factor (BDNF) is important for the maintenance of healthy brain function. Plasma BDNF is lower in people with obesity compared to their lean counterparts, potentially due to differences in metabolic control as acute hyperglycemia reduces cerebral output of BDNF in young, healthy adults. Ingestion of a ketone monoester (KME) drink containing beta‐hydroxybutyrate (β‐OHB) attenuates the glycemic response during an oral‐glucose tolerance test (OGTT) in humans, and increases neuronal expression of BDNF in rodents. Whether ingestion of a KME affects plasma BDNF in humans is currently unknown. The purpose of this study was to examine the effect of KME ingestion before an OGTT on plasma BDNF in normal‐weight adults and adults with obesity. Methods Secondary analyses of two separate studies were performed. Study 1 included lean adults (n=18; M age =25.3 ± 4.3 years; BMI=22.2 ± 2.3 kg/m 2 ) and Study 2 included adults with obesity (n=12; M age =48.8 ± 9.5 years; BMI = 33.7 ± 5.0 kg/m 2 ). In both studies, participants ingested 0.45 mL/kg −1 body weight KME or Placebo 30 minutes prior to completing a 75 g OGTT. β‐OHB, and BDNF were measured via blood samples at fasting baseline (BSL) and 120 min post‐OGTT. Plasma glucose was measured at BSL and every 30 minutes during the OGTT. A 2‐factor repeated measures ANOVA was computed to assess β‐OHB and BDNF responses by time and condition. A paired t‐test was computed to compare glucose area under the curve (AUC). An independent sample t‐test was used to compare fasting plasma BDNF between lean and obese participants. Results Study 1 KME ingestion significantly increased β‐OHB by 800 ± 454% (p<0.001) and blunted plasma glucose AUC by 15.3 ± 12.7% (p<0.001) compared to Placebo. Plasma BDNF significantly decreased post‐OGTT compared to BSL in the Placebo condition (389.3 ± 595.8 pg/mL vs. 718.6 ± 830.8 pg/mL; p=0.018), whereas it was unchanged in the KME condition (469.2 ± 791.8 pg/mL vs. 560.2 ± 689.6 pg/mL; p=0.28). Study 2 KME ingestion significantly increased β‐OHB by 1586 ± 602% (p<0.001) and blunted plasma glucose AUC by 12.3 ± 7.9% (p=0.001) compared to Placebo. In the KME condition, plasma BDNF significantly increased post‐OGTT compared to BSL (188.9 ± 138.2 pg/mL vs. 122.6 ± 129.3 pg/mL; p=0.037), whereas it was unchanged in the Placebo condition (126.4 ± 134.0 pg/mL vs. 143.9 ± 161.9 pg/mL; p=0.18). Fasting plasma BDNF was significantly lower in adults with obesity compared to lean adults (132.8 ± 142.8 pg/mL vs. 639.4 ± 756.8 pg/mL; p=0.002). Conclusions Plasma BDNF is differentially impacted by acute KME ingestion and an OGTT in adults with obesity compared to lean adults. Our findings suggest that KME ingestion may increase BDNF during an OGTT in adults with obesity, whereas KME may protect against hyperglycemia‐induced reductions in BDNF in lean adults. The difference in basal BDNF between groups may suggest that long‐term differences in metabolism and/or body composition impact BDNF. KME may be a strategy for altering plasma BDNF responses during hyperglycemia. Support or Funding Information NSERC Discovery