Exercise training and DNA methylation profile in post-bariatric women: Results from an exploratory study.

Exercise training and bariatric surgery have been shown to independently modulate DNA methylation profile in clusters of genes related to metabolic and inflammatory pathways. This study aimed to investigate the effects of a 6-month exercise training program on DNA methylation profile in women who underwent bariatric surgery. In this exploratory, quasi-experimental study, we analyzed DNA methylation levels by array technology in eleven women who underwent Roux-en-Y Gastric Bypass and a 6-month, three-times-a-week, supervised exercise training program. Epigenome Wide Association Analysis showed 722 CpG sites with different methylation level equal to or greater than 5% (P < 0.01) after exercise training. Some of these CpGs sites were related to pathophysiological mechanisms of inflammation, specially Th17 cell differentiation (FDR value < 0.05 and P < 0.001). Our data showed epigenetic modification in specific CpG sites related to Th17 cell differentiation pathway in post-bariatric women following a 6-months exercise training program.

Epigenetic landscape in blood leukocytes following ketosis and weight loss induced by a very low calorie ketogenic diet (VLCKD) in patients with obesity.

BACKGROUND: The molecular mechanisms underlying the potential health benefits of a ketogenic diet are unknown and could be mediated by epigenetic mechanisms. OBJECTIVE: To identify the changes in the obesity-related methylome that are mediated by the induced weight loss or are dependent on ketosis in subjects with obesity underwent a very-low calorie ketogenic diet (VLCKD). METHODS: Twenty-one patients with obesity (n = 12 women, 47.9 ± 1.02 yr, 33.0 ± 0.2 kg/m2) after 6 months on a VLCKD and 12 normal weight volunteers (n = 6 women, 50.3 ± 6.2 yrs, 22.7 ± 1.5 kg/m2) were studied. Data from the Infinium MethylationEPIC BeadChip methylomes of blood leukocytes were obtained at time points of ketotic phases (basal, maximum ketosis, and out of ketosis) during VLCKD (n = 10) and at baseline in volunteers (n = 12). Results were further validated by pyrosequencing in representative cohort of patients on a VLCKD (n = 18) and correlated with gene expression. RESULTS: After weight reduction by VLCKD, differences were found at 988 CpG sites (786 unique genes). The VLCKD altered methylation levels in patients with obesity had high resemblance with those from normal weight volunteers and was concomitant with a downregulation of DNA methyltransferases (DNMT)1, 3a and 3b. Most of the encoded genes were involved in metabolic processes, protein metabolism, and muscle, organ, and skeletal system development. Novel genes representing the top scoring associated events were identified, including ZNF331, FGFRL1 (VLCKD-induced weight loss) and CBFA2T3, C3orf38, JSRP1, and LRFN4 (VLCKD-induced ketosis). Interestingly, ZNF331 and FGFRL1 were validated in an independent cohort and inversely correlated with gene expression. CONCLUSIONS: The beneficial effects of VLCKD therapy on obesity involve a methylome more suggestive of normal weight that could be mainly mediated by the VLCKD-induced ketosis rather than weight loss.

Temporal dynamics of muscle, spinal and cortical excitability and their association with kinematics during three minutes of maximal-rate finger tapping.

We tested peripheral, spinal and cortical excitability during 3 minutes of unresisted finger tapping at the maximal possible rate, which induced fatigue. Subsequently, we studied the temporal dynamics of muscle fatigue, expressed in the tapping movement profile, and its relationship to neural systems using mixed model analyses. The tapping rate decreased by 40% over the duration of the task. The change in the amplitude of the range of motion was not significant. The excitability of the flexor and extensor muscles of the index finger was tested via evoked potentials obtained with various types of stimulation at various levels of the motor system. The change in spinal excitability with time was evaluated considering the simultaneous changes in muscle excitability; we also considered how spinal excitability changed over time to evaluate cortical excitability. Excitability in the flexor and extensor muscles at the different levels tested changed significantly, but similar excitability levels were observed at notably different tapping rates. Our results showed that only 33% of the decrease in the tapping rate was explained by changes in the excitability of the structures tested in the present work.

Association of MFSD3 promoter methylation level and weight regain after gastric bypass: Assessment for 3 y after surgery.

OBJECTIVES: Genetic predisposition and epigenetic signatures could explain why some individuals regain the weight lost after different obesity treatments. Major facilitator superfamily domain 3 (MFSD3) is a family of membrane-bound solute carriers whose expression has been recently associated with nutrient intake and adipose tissue homeostasis. This study aimed to evaluate a possible association between MFSD3 preoperative methylation pattern and weight regain after bariatric surgery. METHODS: This is a longitudinal study comprising 24 obese (body mass index > 35 m/kg2) women submitted to gastric bypass. Anthropometric measurements were evaluated at preoperative time and 1, 2, and 3 y after surgery, and then weight regain was calculated. Genomic DNA was extracted from leukocytes and was bisulfite modified by specific kits, according manufacturer's instructions. Methylation analysis was performed with the Infinium Human Methylation 450 K bead chip technology, and methylation level was expressed as a ß value ranging from 0 (unmethylated) to 1 (fully methylated). Shapiro-Wilk, repeated-means analysis of variance, Spearman correlation, Mann-Whitney, and independent t tests were used in statistical analysis (P < 0.05). RESULTS: A total of 25% of patients regained significant weight. Weight regain after bariatric surgery was positively correlated with cg00010266 MFSD3 preoperative methylation levels (r = 0.6804, P = 0.0126). Moreover, cg00010266 MFSD3 baseline methylation levels were significantly higher in regainer patients than non-regainers (6.2 ± 1.5 versus 3.9 ± 1.2%, P = 0.026). Patients allocated in the higher cg00010266 MFSD3 preoperative methylation group had higher weight regain (4.1 ± 1.8 versus 6.7 ± 2.2 kg, P = 0.037). CONCLUSIONS: Preoperative hypermethylation of MFSD3 gene is significantly associated with weight regain and a worse response to gastric bypass.

Molecular basis of Gender Dysphoria: androgen and estrogen receptor interaction.

BACKGROUND: Polymorphisms in sex steroid receptors have been associated with transsexualism. However, published replication studies have yielded inconsistent findings, possibly because of a limited sample size and/or the heterogeneity of the transsexual population with respect to the onset of dysphoria and sexual orientation. We assessed the role of androgen receptor (AR), estrogen receptors alpha (ERα) and beta (ERß), and aromatase (CYP19A1) in two large and homogeneous transsexual male-to-female (MtF) and female-to-male (FtM) populations. METHODS: The association of each polymorphism with transsexualism was studied with a twofold subject-control analysis: in a homogeneous population of 549 early onset androphilic MtF transsexuals versus 728 male controls, and 425 gynephilic FtMs versus 599 female controls. Associations and interactions were investigated using binary logistic regression. RESULTS: Our data show that specific allele and genotype combinations of ERß, ERα and AR are implicated in the genetic basis of transsexualism, and that MtF gender development requires AR, which must be accompanied by ERß. An inverse allele interaction between ERß and AR is characteristic of the MtF population: when either of these polymorphisms is short, the other is long. ERß and ERα are also associated with transsexualism in the FtM population although there was no interaction between the polymorphisms. Our data show that ERß plays a key role in the typical brain differentiation of humans. CONCLUSION: ERß plays a key role in human gender differentiation in males and females.