β-hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-β-hydroxybutyrylation

https://doi.org/10.1016/j.bbrc.2017.05.184Get rights and content

Highlights

  • β-hydroxybutyrate and H3K9bhb were reduced in brain of mice after stress.

  • Exogenous β-hydroxybutyrate ameliorated depression behavior.

  • β-hydroxybutyrate reversed the decrease of H3K9bhb and BDNF in vivo and vitro.

Abstract

Epigenetics regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network. Metabolite changes in vivo after stress contribute to histone modification. Histone3-lysine9-β-hydroxybutyrylation (H3k9bhb), a novel histone modification mark induced by β-hydroxybutyrate, may participate in the development of depression. To examine the role of H3k9bhb in depression, experiments were performed on mice and cells. H3k9bhb were reduced in the brain of depressive mice. Exogenous β-hydroxybutyrate ameliorated depressive behaviors and reversed the reduction of H3K9bhb and BDNF. We showed that H3k9bhb played a role in depression, and firstly linked BHB and BDNF via H3k9bhb. Our findings emphasized the crucial role of metabolic regulation on epigenetics in depression.

Introduction

Depression, also known as major depressive disorders (MDD), is the most commonly diagnosed neuropsychiatric disorders with characteristics of low mood, anhedonia, hopelessness, and even suicidal intentions. Its high incidence made the exploration of etiology and new antidepressants to be desirable and crucial [1], [2]. A lot of explorations suggest that the debilitating and prevalent psychiatric illnesses have genetic, environmental and epigenetic underpinnings [3]. Family-based studies suggest that depression is a familial disorder with a heritability of about 40% [4]. While genome-wide association studies (GWAS) showed that no SNPs (single nucleotide polymorphism) significantly act as main effects of MDD [5]. Epidemiological studies have revealed that environmental factors, such as stressful life events, act as important determinants of susceptibility and resilience to MDD [5], [6]. Based on those previous reports, the mechanism of MDD is still unclear. Recently, increased evidences demonstrated the epigenetic factor as a new mechanism from a perspective looking beyond conventional ‘Gene + Environment’ etiological paradigms [7], [8]. Epigenetics provide a pathogenesis route via which the environment can directly interact with the genome by the modifications of DNA or/and histones without a change in DNA sequence [9], [10]. DNA methylation, histone methylation and histone acetylation are the main epigenetic modifications associated with MDD in the past decades [9], [10], [11]. H3K9bhb, as a new type of histone modifications directly induced by β-hydroxybutyrate (BHB), was preferentially associated with gene promoters to activate gene up-regulation during prolonged fasting [12]. It may be associated with depression that accompanied with obvious metabolic disorder.

BHB is the main constituent of ketone bodies synthesized mainly in the liver, and also in the brain [13]. The concentration of BHB in the brain increased after starvation [14], and reduced during inflammatory state [15]. Metabolic and neuroendocrine disorders caused by environmental stress may affect the BHB metabolism in the brain [16]. Besides being used to treat epilepsy, BHB plays a neuroprotective role in neurodegenerative diseases and psychotic disorders [17], [18], [19], and has been demonstrated antidepressant effect in depression [20]. It is highly conceivable that BHB might act to increase the levels of BDNF (Brain derived neurotrophic factor) [21], [22]. BDNF is a prevalent growth factor in the brain, and widely implicated in psychiatric diseases. BDNF is downregulated in MDD patients and the downregulation can be rescued by antidepressants [23]. However, the detailed mechanism of obvious BDNF changes in MDD is also undetermined. Therefore, we proposed our hypothesis: BHB and H3k9bhb reduced in depression and depressive behaviors were rescued by exogenous BHB; the mechanism of antidepressant effects of BHB may be associated with the modification of BDNF promoters by H3k9bhb. We performed our experiments with different mouse models of depression and primary cultured neurons.

Section snippets

Animals

Male ICR mice (20–25 g) from SLAC Company (Shanghai, China) were maintained at a temperature of 25 ± 2 °C with a 12 h light/dark cycle. The present animal research were approved by the University Committee on Animal Care of Soochow University and conducted in accordance with the guidelines of Animal Use and Care of the National Institutes of Health.

Spatial restraint stress

Mice were randomly assigned into control group (Con) and spatial restraint stress group (Str). Stress group mice were individually placed into a

The level of H3k9bhb decreased in different depressive mouse models

MDD induced by stress events or social defeats is usually accompanied with hypothalamic-pituitary-adrenal (HPA) axis activation [26] and fatty acid metabolic disorders [27]. Previous studies have demonstrated that chronic administration of dexamethasone (a synthetic glucocorticoid steroid) via intraperitoneal injection and spatial restraint stress lead to depression-like response in mice [24], [28], [29]. To determine the role of H3k9bhb in depression, both dexamethasone (Dex) and spatial

Discussion

In our study, the concentrations of BHB were reduced after depression in mice, and the level of H3k9bhb was also decreased. Exogenous BHB improved depressive behaviors and alleviated the reduction of H3k9bhb and BDNF. Increasing evidences implicate that altered metabolic states influence histone modifications and then induced changes in gene expression [30]. Metabolites such as NAD (+), S-adenosyl methionine, acetyl-CoA and a growing list of other acyl-CoA derivatives play crucial roles in

Conflict of interest

The authors declare that there is no conflict of interests.

Acknowledgements

The study was supported by the grants from Natural Science Foundation of China (81601154) and the Priority Academic Program Development of Jiangsu Higher Education Institutions of China.

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