Comparison of the effects of BDNF/TRKB signalling on metabolic biomarkers in the liver of sedentary and trained rats with normal and knockout BDNF genotypes

Abstract

Introduction: The effect of brain-derived neurotrophic factor (BDNF) on the modulation of metabolic processes in the liver is poorly understood. Therefore, the aim of this study was to investigate whether hepatic concentrations or activities of metabolic biomarkers depend on altered BDNF/TrkB content in the liver, resulting from different BDNF genotypes of rats. In addition, it was assessed whether 5-week moderate endurance training modifies the levels of BDNF/Trk-B signaling and studied hepatic markers. Methods: Experiments were performed on wild-type and heterozygous BDNF knockout (HET, SD-Bdnf) rats, which were divided into four groups: control with normal genotype (Bdnf+/+), control with BDNF knockout genotype (Bdnf+/-), trained with normal genotype (Bdnf+/+T) and trained with BDNF knockout genotype (Bdnf +/-T). BDNF/TrkB concentrations as well as selected metabolic biomarkers including lipids-total cholesterol (CHOL), low-density lipoprotein (LDL), triglycerides (TG); enzymes-alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP); hormones-insulin (INS) and leptin (LEPT) as well as interleukin-6 (IL-6) as regeneration indicator were measured directly in liver homogenates. Results and Discussion: The study showed that Bdnf+/- rats exhibited reduced BDNF/TrkB signaling (BDNF, p < 0.0001; Trk-B, p = 0.0005), altered lipid levels (CHOL, p < 0.0001; LDL, p < 0.0001; TG, p = 0.0006) and reduced hepatic ALAT (p = 0.0004) and GGT (p < 0.0001) activity, which may contribute to hepatic steatosis and obesity, as well as indicate impairment of specific metabolic pathways in the liver. Interestingly, endurance training did not alter hepatic BDNF and TrkB content, but improved ALAT (p = 0.0366) and ASAT (p = 0.0191) activities and increased hepatic IL-6 (p = 0.0422) levels in Bdnf +/- rats, suggesting enhanced liver regeneration in animals with BDNF allele loss.

Keywords: BDNF; endurance training; knockout genotype; liver; rats.

FIGURE 1

The mean values (±SD) of body weights (A) and liver weights (B) of rats from control (left side) and trained (right side) groups. Bdnf+/+ rats are indicated by black, while Bdnf+/− rats are indicated by grey. Comparisons between groups were made by two-way ANOVA. (G) genotype (Bdnf+/+ genotype vs. Bdnf+/− genotype); T—training (control vs. training); G x T—the interaction between genotype and training. For significant interactions Tukey’s post hoc test was performed. Significant results are denoted by p, while non-significant results are denoted by ns. Effects for body weights: Genotype—F = 56.84, p < 0.0001, ηp2 = 0.63; Training—F = 14.76, p = 0.0005, ηp2 = 0.31; Genotype x Training—F = 2.35, p = 0.1351, ηp2 = 0.07. Effects for liver weights: Genotype - F = 29.30, p < 0.0001, ηp2 = 0.47; Training—F = 0.92, p = 0.0005, ηp2 = 0.03; Genotype x Training - F = 2.18, p = 0.1494, ηp2 = 0.06.

FIGURE 2

The mean values (±SD) of BDNF (A) and Trk-B (B) concentrations in the liver of rats from control (left side) and trained (right side) groups. Control and trained Bdnf+/+ groups are indicated by black square, while control and trained Bdnf+/− groups are indicated by white square. Comparisons between groups were made by two-way ANOVA. (G) genotype (Bdnf+/+ genotype vs. Bdnf+/− genotype); T—training (control vs. training); G x T, the interaction between genotype and training. For significant interactions Tukey’s post hoc test was performed. Post-hoc results: * = significant difference between control rats with Bdnf+/+ genotype and control rats with Bdnf+/− genotype (p = 0.0006); # = significant difference between trained rats with Bdnf+/+ genotype and control rats with Bdnf+/− genotype (p = 0.0351). Detailed results of performed tests are given in Table 1.

FIGURE 3

The mean values (±SD) of CHOL (A), LDL (B) and TG (C) concentrations in the liver of rats from control (left side) and trained (right side) groups. Control and trained Bdnf+/+ groups are indicated by black square, while control and trained Bdnf+/− groups are indicated by white square. Comparisons between groups were made by two-way ANOVA. (G) genotype (Bdnf+/+ genotype vs. Bdnf+/− genotype); T—training (control vs. training); G x T, the interaction between genotype and training. Significant results are denoted by p, while non-significant results are denoted by ns. Detailed results of performed tests are given in Table 1.

FIGURE 4

The mean values (±SD) of ALAT (A), ASAT (B), ALP (C), GGT (D) and LDH (E) activities in the liver of rats from control (left side) and trained (right side) groups. Control and trained Bdnf+/+ groups are indicated by black square, while control and trained Bdnf+/− groups are indicated by white square. Comparisons between groups were made by two-way ANOVA. (G) genotype (Bdnf+/+ genotype vs. Bdnf+/− genotype); T—training (control vs. training); G x T, the interaction between genotype and training. significant results are denoted by p, while non-significant results are denoted by ns. For significant interactions Tukey’s post hoc test was performed. Post-hoc results: * = significant difference between control rats with Bdnf+/+ genotype and control rats with Bdnf+/− genotype (p = 0.0003); # = significant difference between trained rats with Bdnf+/+ genotype and control rats with Bdnf+/− genotype (p = 0.0014); $ = significant difference between trained rats with Bdnf+/− genotype and control rats with Bdnf+/− (p = 0.0366). Detailed results of performed tests are given in Table 1.

FIGURE 5

The mean values (±SD) of INS (A) and LEPT (B) concentrations in the liver of rats from control (left side) and trained (right side) groups. Control and trained Bdnf+/+ groups are indicated by black square, while control and trained Bdnf+/− groups are indicated by white square. Comparisons between groups were made by two-way ANOVA. (G) genotype (Bdnf+/+ genotype vs. Bdnf+/− genotype); T - training (control vs. training); G x T, the interaction between genotype and training. Significant results are denoted by p, while non-significant results are denoted by ns. Detailed results of performed tests are given in Table 1.

FIGURE 6

The mean values (±SD) of IL-6 (A) concentration in the liver of rats from control (left side) and trained (right side) groups. Control and trained Bdnf+/+ groups are indicated by black square, while control and trained Bdnf+/− groups are indicated by white square. Comparisons between groups were made by two-way ANOVA. G—genotype (Bdnf+/+ genotype vs. Bdnf+/− genotype); T - training (control vs. training); G x T, the interaction between genotype and training. For significant interactions Tukey’s post hoc test was performed. Post-hoc results: ▲ = significant difference between trained rats with Bdnf+/− genotype and control rats with Bdnf+/+ genotype (p = 0.0354); ● = significant difference between trained rats with Bdnf+/− genotype and trained rats with Bdnf+/+ genotype (p = 0.0201); $ = significant difference between trained rats with Bdnf+/− genotype and control rats with Bdnf+/− (p = 0.0422). Detailed results of performed tests are given in Table 1.