Methylation Status of Exon IV of the Brain-Derived Neurotrophic Factor (BDNF)-Encoding Gene in Patients with Non-Diabetic Hyperglycaemia (NDH) before and after a Lifestyle Intervention.

Helene A Fachim,J Martin Gibson,Nagaraj Malipatil,Gabriela Y Cortés,Kirk Siddals,Adrian H Heald,Rachelle Donn,Caroline F Dalton

doi:10.3390/epigenomes6010007

Abstract

BDNF signalling in hypothalamic neuronal circuits is thought to regulate mammalian food intake. In light of this, we investigated how a lifestyle intervention influenced serum levels and DNA methylation of BDNF gene in fat tissue and buffy coat of NDH individuals. In total, 20 participants underwent anthropometric measurements/fasting blood tests and adipose tissue biopsy pre-/post-lifestyle (6 months) intervention. DNA was extracted from adipose tissue and buffy coat, bisulphite converted, and pyrosequencing was used to determine methylation levels in exon IV of the BDNF gene. RNA was extracted from buffy coat for gene expression analysis and serum BDNF levels were measured by ELISA. No differences were found in BDNF serum levels, but buffy coat mean BDNF gene methylation decreased post-intervention. There were correlations between BDNF serum levels and/or methylation and cardiometabolic markers. (i) Pre-intervention: for BDNF methylation, we found positive correlations between mean methylation in fat tissue and waist-hip ratio, and negative correlations between mean methylation in buffy coat and weight. (ii) Post-intervention: we found correlations between BDNF mean methylation in buffy coat and HbA1c, BDNF methylation in buffy coat and circulating IGFBP-2, and BDNF serum and insulin. Higher BDNF % methylation levels are known to reduce BNDF expression. The fall in buffy coat mean BDNF methylation plus the association between lower BDNF methylation (so potentially higher BDNF) and higher HbA1c and serum IGFBP-2 (as a marker of insulin sensitivity) and between lower serum BDNF and higher circulating insulin are evidence for the degree of BDNF gene methylation being implicated in insulinisation and glucose homeostasis, particularly after lifestyle change in NDH individuals.

Highlights

Pre-intervention results: We identified a positive correlation between Brain-derived neurotrophic factor (BDNF) mean methylation in adipose tissue and waist/hip ratio (r = 0.528, p = 0.017) (Figure 2a) and negative correlations between adipose BDNF mean methylation and total cholesterol (r = −0.552, p = 0.012) (Figure 2b)
We found a negative correlation between BDNF mean methylation in buffy coat and weight (r = −0.482, p = 0.037) (Figure 2c)
3b)above for thecorrelations whole group. Removing those levels individuals who gain of weight or more, were still sigthose individuals who gain of weight or more, the above correlations were still signifnificant, and we found a negative correlation between buffy coat BDNF mean methylaicant, and we found a negative correlation between buffy coat mean methylation tion and serum insulin-like growth factor binding protein-2 gene (IGFBP-2) levels

Summary

Introduction

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that promote neuronal differentiation, adult neurogenesis, learning, memory [1,2] and neural plasticity [3,4]; it is produced and released by the brain into circulation. In addition to these roles, BDNF has been identified as a key component of the hypothalamic pathway that controls body weight, food intake, and energy homeostasis in mammals [5]. BDNF treatment in obese and diabetic rodents significantly reduces blood glucose level, attenuates body weight gain and food intake, and enhances energy and glucose metabolism [8,9]

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Results

Conclusion