Interactive actions of Bdnf methylation and cell metabolism for building neural resilience under the influence of diet

Highlights

• Western diet promotes methylation of the Bdnf gene with behavioral detriments.

• Omega-3 fatty acids counteract the effects of the Western diet.

• Diets orchestrate key interactions between metabolic signals and Bdnf methylation.

• Changes in Bdnf methylation may serve to build an “epigenetic memory”.

Abstract

Quality nutrition during the period of brain formation is a predictor of brain functional capacity and plasticity during adulthood; however it is not clear how this conferred plasticity imparts long-term neural resilience. Here we report that early exposure to dietary omega-3 fatty acids orchestrates key interactions between metabolic signals and Bdnf methylation creating a reservoir of neuroplasticity that can protect the brain against the deleterious effects of switching to a Western diet (WD). We observed that the switch to a WD increased Bdnf methylation specific to exon IV, in proportion to anxiety-like behavior, in Sprague Dawley rats reared in low omega-3 fatty acid diet, and these effects were abolished by the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine. Blocking methylation also counteracted the reducing action of WD on the transcription regulator CTCF binding to Bdnf promoter IV. In vitro studies confirmed that CTCF binding to Bdnf promoter IV is essential for the action of DHA on BDNF regulation. Diet is also intrinsically associated to cell metabolism, and here we show that the switch to WD downregulated cell metabolism (NAD/NADH ratio and SIRT1). The fact that DNA methyltransferase inhibitor did not alter these parameters suggests they occur upstream to methylation. In turn, the methylation inhibitor counteracted the action of WD on PGC-1α, a mitochondrial transcription co-activator and BDNF regulator, suggesting that PGC-1α is an effector of Bdnf methylation. Results support a model in which diet can build an “epigenetic memory” during brain formation that confers resilience to metabolic perturbations occurring in adulthood.

Introduction

An increasing body of evidence suggests that a large number of neuropsychiatric disorders are the result of complex interactions between genetic factors and the environment (Dauncey, 2012) and that epigenetic mechanisms may mediate these effects (Choi and Friso, 2010). Diet is one of the most crucial factors for species survival and adaptation, and here we examine the possibility that foods influence the brain by building an “epigenetic memory” that could be instrumental in resistance to neurological challenges. The strong dependence of the brain on energy implies that metabolic stimuli such as dietary factors have the intrinsic ability to influence brain plasticity (Agrawal et al., 2014) and epigenetic variability.

BDNF malfunction has been implicated in the pathology of neurological and psychiatric disorders (Greenberg et al., 2009, Zuccato and Cattaneo, 2009). Bdnf transcription and function are under regulation of DNA methylation (Martinowich et al., 2003), and abnormal epigenetic regulation of the Bdnf gene is emerging an underlying mechanism for various neurological disorders (Boulle et al., 2012). DNA methylation is the one of most stable forms of epigenetic variability involved in the control of transcription and function of selected genes (Godfrey et al., 2007, Moore et al., 2013) can repress Bdnf gene expression via transcriptional repressor methyl-CpG-binding protein (MeCP2) (Chen et al., 2003, Ma et al., 2009). Since BDNF can act on plasticity and metabolism it is termed a “metabotrophin” (Gomez-Pinilla, 2008, Gomez-Pinilla et al., 2008), and these inherent properties of BDNF may be crucial to translating the effects of foods on the brain. For example, one potential intermediary may be nicotinamide adenine dinucleotide (NAD +), a cofactor in oxidation/reduction (hydride transfer) reactions. The action of NAD on energy regulation is under the scope of the sirtuin family of proteins (Cantó and Auwerx, 2012). SIRT1 influences the activity of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), which is one of the most versatile metabolic transcriptional co-activators of genes involved in energy metabolism (Nemoto et al., 2005, Rodgers et al., 2008) and mitochondrial function (Finkel, 2006).

The omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) is associated with reduced risk of Alzheimer's disease, schizophrenia and depression (Young and Conquer, 2005). On the other hand, dietary intakes of saturated fats do the opposite (Sánchez-Villegas et al., 2011, Tyagi et al., 2013). The current studies were designed to determine whether exposure to omega-3 fatty acids during the whole period of brain formation promotes epigenetic variability and protection against metabolic perturbations. Results introduce the idea that metabolism and epigenetics are closely associated events that contribute to program an epigenetic memory through long-term brain plasticity. These results provide fundamental information for the design of therapeutic applications and public health policy.