Impaired brain plasticity in obesity: effects of bariatric surgery and gut hormones

Background and aims: Obesity and diabetes are associated with reduced plasticity in the hippocampus and impairment of memory and learning. It is still unclear whether obesity can alter plasticity in the sensory cortex. Gut hormones play a crucial role in neuroplasticity (NP) but to which extent it can mediate obesity’s effects on NP and cognition is still poorly evaluated. The aims of the study were to evaluate: i) the effect of obesity and bariatric surgery (RYGB) on NP ii) the relationship between NP and gut hormones (GLP-1, GIP and VIP) changes 6 months (6m)after RYGB iii) the relationship between NP, BDNF, Leptin and cognitive performance Materials and methods: NP was assessed testing binocular rivalry be- tween orthogonal gratings (size: 2°, contrast: 50%, SF: 2cpd) before and after 2 h of monocular deprivation (index of brain plasticity in the visual cortex). NP evaluation has been performed on 20 healthy volunteers (NS) (age 26 ± 10 years, BMI 21.7 ± 2.6 kg/m2) and 31 obese subjects (OB) (age: 40 ± 11 years; BMI: 41.6 ± 6.7 kg/m2) in fasting condition. A sub- group of OB (n = 13; BMI 45.8 ± 4.9 kg/m2; age 43.7 ± 9.5 years; HbA1c 41.5 ± 5.4 mmol/mol) underwent a 75 g OGTT before and 6m after RYGB. NP was performed at baseline, 1, 3 and 6 m after RYGB. Gut hormones, BDNF, leptin and cognitive performance were assessed at baseline and 6 m after RYGB Results: In the whole population NP was lower in OB as compared to NS (0.12 ± 0.05 vs. 0.04 ± 0.08, p < 0.0001) and NP was inversely correlated with BMI (r = −0.55; p < 0.001). In the OB subgroup 6 m after RYGB a significant BMI reduction (45.8 ± 4.9 to 34.3 ± 1.6 kg/m2; p < 0.001) was associated withimproved glucose metabolism (HOMA-IR: 4.7 ± 0.9 to 1.6 ± 0.4; P = 0.006; Disposition Index: 0.07 ± 0.02 to 0.81 ± 0.30 mUI × ml−1/mg × dl−1 × 1/mUI × ml−1; P < 0.05). NP was progres- sively restored (ANOVA: F(3.24) = 5.7, p = 0.002) with a 10 fold increase of NP 6 m after RYGB (0.01 ± 0.03 to 0.11 ± 0.04; p = 0.008). Post- OGTT GLP-1 increased (5336 ± 2263 to 11132 ± 3412 pmol/l × 120 min; p < 0.05) as well as GIP (4140 ± 3659 to 5791 ± 4537 pg/ml × 120 min; p = 0.01). The NP increase was correlated to active GLP-1 and negatively with GIP increase(p < 0.05). VIP levels did not change 6 m after RYGB with no correlation with NP. Fasting plasma leptin decreased (73.8 ± 45.5 to 14.3 ± 5.9 pmol/l; p < 0.008) and it was inversely corre- lated with NP increase (p < 0.05). Baseline BDNF was inversely corre- lated with fasting insulin (r = −0.76; p = 0.007) and it did not change after 6m RYGB. Post-RYGB BDNF inversely correlated with NP (p < 0.05) but positively with both total and active GLP1 (p < 0.05). NP correlated with cognitive performance (p < 0.05). In a multiple linear regression analysis, addition of post-RYGB gut hormones, BDNF and Leptin to BMI and fasting glucose improved the r2 associated to post-RYGB NP (r2 change: 0.881; F change: 10732.19; p = 0.007) Conclusion: Obesity is associated with abnormal NP in visual cortex that can be reversed by weight-loss following bariatric surgery, supporting a strong effect of peripheral metabolism on early sensory plasticity and function. The relationship between NP increase, circulating gut hor- mones, BDNF and Leptin suggest a potential role of these hormones in the NP restoration and cognitive function in humans