Carbohydrate-Restricted Diet and Exercise Increase Brain-Derived Neurotrophic Factor and Cognitive Function

Brain-derived neurotrophic factor, or BDNF, is a group of proteins that plays a crucial role in nervous system function, development, and upkeep (1). Multiple lines of research have linked impairments in metabolic health to decreased levels of BDNF and vice versa, leading some to describe BDNF as a “metabotropin” (2). The relationship between BDNF and metabolic impairment seems to be bidirectional. Mouse studies have shown that artificially lowering BDNF levels leads to increased food intake and obesity (3), while BDNF infusions in humans have been tested to reduce body weight and improve glucose control (4). Individuals with diabetes and the metabolic syndrome, as well as those eating diets high in both fat and carbohydrate, have lower BDNF levels than healthy controls (5). Exercise and caloric restriction have independently been shown to increase BDNF, and with it, some measures of cognitive function (6).

This trial tested specifically whether the beneficial effects of diet and exercise on BDNF and other measures of cognitive function are additive in metabolically unhealthy individuals. Four men and eight women (mean age: 40.9) were recruited, all of whom had metabolic syndrome. Subjects were placed on two four-week interventions in random order, separated by a four-week washout period. In both phases, subjects followed a low-carbohydrate paleolithic diet, which discouraged processed foods, dairy, and most grains and emphasized meat, certain vegetables, fruit, and nuts while limiting total carbohydrate intake to less than 50 grams per day. Subjects were not told to deliberately change total calorie intake. In one phase, subjects were told to remain sedentary. In the other phase, they were placed on a HIIT (high-intensity interval training) regimen that involved 10 60-second cycling bouts with 60 seconds of rest between rounds. The exercise aimed for approximately 90% maximal heart rate and occurred three days each week.

Subjects were compliant with the prescribed diet, reporting significant reductions in carbohydrate and total calorie intake (7). The reporting was supported by moderately elevated ketone levels in all subjects. Calorie intake decreased by approximately 800 calories per day from baseline, which is similar to what has been observed in previous studies testing carbohydrate-restricted diets in free-living subjects (8).

Both interventions led to significant increases in BDNF compared to baseline. The addition of HIIT led to significantly greater BDNF elevations than a change in diet alone (38% and 20% increases from baseline for the HIIT and sedentary interventions, respectively). Similar effects were seen in other measures of cognitive function, with both arms improving cognitive speed and flexibility (as assessed by Stroop test) as well as cognitive function (as assessed by MOS-CFS). Again, the diet-plus-HIIT intervention led to significantly greater changes than diet alone. Subjects showed improvements in body fat, fasting glucose, fasting triglycerides, and insulin sensitivity as a result of these interventions, and the degree of improvement in these metabolic measures was weakly, but significantly, correlated with changes in serum BDNF. This suggests carbohydrate and/or calorie restriction and high-intensity exercise have significant and additive beneficial effects on multiple measures of cognitive function and performance. Note, however, that because subjects significantly decreased the number of calories they consumed, this study cannot determine to what extent carbohydrate restriction or calorie restriction specifically affects BDNF levels.

Previous studies have indicated caloric restriction improves BDNF levels and a variety of measures of cognitive function (9). Exercise alone has been shown to improve cognitive function, potentially via beneficial effects on BDNF levels (10). These effects have been shown to be intensity-dependent, with higher-intensity exercise leading to greater improvements. This may be due to direct links between muscular contraction and increased BDNF levels (11). The cognitive impairments observed in individuals with insulin resistance and/or the metabolic syndrome may be similarly mediated by reduced BDNF levels in these individuals, which suggests the metabolic improvements seen in these subjects may have directly influenced their BDNF levels (12).

Overall, these results indicate both diet and exercise lead to significant improvements in cognitive function and performance in metabolically unhealthy individuals. Previous research consistent with these results suggests the specific intervention used here — a combination of carbohydrate and calorie restriction alongside high-intensity exercise — may be maximally effective in improving cognitive function and performance.

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Notes

1. Neurotrophins: Roles in neuronal development and function
2. Immunocytochemical localization of TrkB in the central nervous system of the adult rat; Role of exercise-induced brain-derived neurotrophic factor production in the regulation of energy homeostasis in mammals; The metabotrophic NGF and BDNF: an emerging concept
3. Conditional deletion of brain-derived neurotrophic factor in the postnatal brain leads to obesity and hyperactivity; A possible link between BDNF and mTOR in control of food intake; Brain-derived neurotrophic factor and obesity in the WAGR syndrome
4. Brain-derived neurotrophic factor regulates glucose metabolism by modulating energy balance in diabetic mice
5. Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: A role for NGF and BDNF in cardiovascular disease?; Brain-derived neurotrophic factor (BDNF) and type 2 diabetes; A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning; Evaluation of the effect of caloric restriction on serum BDNF in overweight and obese subjects: preliminary evidences
6. The concentrations of serum, plasma and platelet BDNF are all increased by treadmill VO2max performance in healthy college men; High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise
7. As previously noted on CrossFit.com, self-reported measures of dietary intake often deviate from objectively measured intake patterns. In this case, the subjects’ reporting was confirmed by elevations in ketone levels, which suggests that even if reporting error occurred, the subjects remained within general bounds of compliance. However, this trial is best interpreted as evidence of the general benefits of carbohydrate and/or calorie restriction rather than definitive evidence that the observed effects are attributable to the specific dietary prescription.
8. Comparison of a very low-carbohydrate and low-fat diet on fasting lipids, LDL subclasses, insulin resistance, and postprandial lipemic responses in overweight women
9. Carbohydrate restriction has a more favorable impact on the metabolic syndrome than a low fat diet
10. Coupling energy metabolism with a mechanism to support brain-derived neurotrophic factor-mediated synaptic plasticity; Exercise reverses the harmful effects of consumption of a high-fat diet on synaptic and behavioral plasticity associated to the action of brain-derived neurotrophic factor; The combined effects of exercise and foods in preventing neurological and cognitive disorders
11. The effect of acute exercise on serum brain-derived neurotrophic factor levels and cognitive function; High-intensity interval training evokes larger serum BDNF levels compared with intense continuous exercise; Exercise induces Hhppocampal BDNF through a PGC-1α/FNDC5 pathway
12. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance; Regulation of brain-derived neurotrophic factor mRNA levels in hippocampus by neuronal activity