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Gharipour, M.; Barekatain, M.; Sung, J.; Emami, N.; Sadeghian, L.; Dianatkhah, M.; Sarrafzadegan, N.; Jahanfar, S. Obesity and Mood Disorders. Encyclopedia. Available online: (accessed on 19 June 2024).
Gharipour M, Barekatain M, Sung J, Emami N, Sadeghian L, Dianatkhah M, et al. Obesity and Mood Disorders. Encyclopedia. Available at: Accessed June 19, 2024.
Gharipour, Mojgan, Majid Barekatain, Johoon Sung, Naghmeh Emami, Ladan Sadeghian, Minoo Dianatkhah, Nizal Sarrafzadegan, Shayesteh Jahanfar. "Obesity and Mood Disorders" Encyclopedia, (accessed June 19, 2024).
Gharipour, M., Barekatain, M., Sung, J., Emami, N., Sadeghian, L., Dianatkhah, M., Sarrafzadegan, N., & Jahanfar, S. (2020, September 30). Obesity and Mood Disorders. In Encyclopedia.
Gharipour, Mojgan, et al. "Obesity and Mood Disorders." Encyclopedia. Web. 30 September, 2020.
Obesity and Mood Disorders

Obesity and mood disorders are considered as the most prevalent morbidities in many countries. We suppose that epigenetic mechanisms may induce higher rates of obesity in subjects who suffer from mood disorders. In this study, we focused on the potential roles of DNA methylation on mood disorders and obesity development.

depression epigenetics mood disorders obesity.

1. Introduction

Obesity and mood disorders are considered as the most prevalent morbidities in developed and developing countries [1][2][3]. The worldwide prevalence of obesity has nearly tripled since 1975. In 2016, more than 650 million adults were obese and 38 million children under the age of 5 were overweight or obese in 2019 [4]. The prevalence of mood disorders differs based on sex and disease. For example, the prevalence of major depressive disorder (MDD) and anxiety are 17.4% and 18.2% in men, 22.7% and 23.6 in women, respectively [5].

A combination of genetics and environmental factors affect the incidence and development of obesity and mood disorders [6][7]. The type and amount of food consumed during depression appeared to be significantly correlated and could affect the weight in a long time [8]. It has been well-established that 12% of the responsible genes for obesity are shared with depression [9], and changes in the mutual pathways of the shared genes could lead to altering the pathological eating behavior in patients with mood disorders. In addition, antidepressant drugs can alter body mass indexes [10][11][12].

One of the possible biological changes that could be responsible for the co-occurrence of these disorders might be epigenetic changes [13][14]. Epigenetics could legitimize modifications in the chromatin level, which alters the expression of genes involved in obesity and mood disorder [15][16]. Epigenetics could explain complex interactions between the genome and the environment. Epigenetic modifications, such as DNA methylation and histone modification, alter DNA accessibility and chromatin structure, thereby regulating patterns of gene expression [17]. For example, increasing the methylation of DNA reduces the expression of genes, while decreasing methylation is associated with increased gene expression [18]. DNA methylation occurs in the whole genome but could play an important role in repressing gene transcription when affecting the gene promoter (especially in the CpG islands, shore, and shelves) [19]. The relationship between DNA methylation and obesity and mood disorders has been reported previously [20][21][22][23][24].

2. Discussion

Our results revealed three overlapped genes with different methylated patterns during obesity or mood disorders, which can assist us to understand better the molecular pathophysiology of these disorders. In the further step, we attempted to identify the possible pathways that could be involved in obesity and mood disorders through the overlap genes.

In the era of the increasing prevalence of obesity and mood disorders, especially in both developing and developed world, results from our systematic review suggest an interplay between genetic susceptibility, diet, epigenetics, metagenomics, and the environment [25][26].

Evidently, obesity was found to increase the risk of depression, and depression was found to be predictive of developing obesity. Remarkably, obese persons had a 55% increased risk of developing depression over time, whereas depressed persons had a 58% increased risk of becoming obese. Neuroendocrine disturbances may also lead to depression, which in turn would cause an increase in weight over time by dysregulated stress systems or through unhealthy lifestyles. It is also possible that obesity, by its adverse effects on self-image or somatic consequences, results in the development of depression over time [27]. So, scientists struggled to find responsible genes through genome-wide association studies (GWAS) to identify the risk associated with single nucleotide polymorphisms, which might also be responsible for the co-occurrence of two conditions.

In recent years, scientific documents proved that genes are not responsible for disease by themselves, and the interaction of genes and environment is better determinants for phenotypes. Accordingly, the latest researches are likely to focus on epigenome-wide association studies (EWAS). The advantages of EWAS is considering the interaction of both genes and environments. The information gained from GWAS and EWAS has potential applications in disease control and treatment. In this study, we merely focused on DNA methylation, which could cause alterations in gene expressions and changes in the pathophysiology of diseases. We found three overlapped genes between mood disorders and obesity “TAPBPSORBS2, and BDNF.” As these genes were found through published results of EWAS, we will discuss canonical pathways that might be involved in co-occurrence mood disorders and obesity.

TAPBP: The TAPBP gene is located in chromosome 6 and encodes tapsin; a transmembrane glycoprotein that mediates the interaction between newly assembled major histocompatibility complex (MHC) class I molecules. MHC1 is a transporter associated with antigen processing (TAP), which is required for the transport of antigenic peptides across the ER membrane [28][29]TAPBP-mutant mice have defects in the expression of MHC class I, antigen presentation, and immune responses. Remarkably, Cui et al. found that the expression levels of HLA-ABC were upregulated even in the TAPBP knock-out cells by the interferon treatment, and immune rejection was reduced in TAPBP-deficient hESC line. Potent inflammatory molecules such as eicosanoids are able to upregulate TAPBP [30][31].

The important role of TAPBP is not recognized in the past in both obesity and mood disorders, and just in recent years. The results of EWAS-approved methylation in this gene could play a crucial role in these conditions. Murphy et al. identified epigenetic changes such as differentiated methylated regions (DMR) located in the third intron of the TAPBP gene that is related to the major depressive disorder and suicide [32]. Another study demonstrated hypermethylated CpG sites observed in the promoter region of TAPBP in obese and overweight subjects. These results confirmed by NEST cohort results revealed differentially methylated CpGs of TAPBP gene is related to the maternal pre-pregnancy obesity [33]. In vitro experiments revealed higher methylation levels of TAPBP, such as those found in above-mentioned studies might decrease tapsin via reduced transcriptional activity, leading to impaired immune responses and lower CD8 + T-cell responses [34][35][36]. In mice, tapsin is activated by the cytokines like IFN-γ and IFN-β, and to a lesser extent, TNF-α [36].

These results were very thought-provoking and cited several times by others and unlocked doors to the diagnosis of pathophysiology and new treatments.

TAPBP is linked to both mood disorders and obesity through the JNK pathway. This pathway plays a vital role in the inflammatory response and oxidative stress [34]. Briefly, stress-induced JNK activation occurs in the adipose and liver tissue of obese mice, whether obesity is induced by a high-fat diet or genetically through leptin deficiency (obese/obese mice). Insulin resistance in obese mice through ER stress-mediated JNK pathway is induced by the phosphorylation of insulin receptor substrate 1 (IRS1), which impairs insulin action and causes insulin resistance [35].

Interestingly, in the different tissues of obese subjects, inflammatory factors can be observed to cause continuous activation of JNK. The activated JNK acts on nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) to produce more inflammatory factors, further reducing the sensitivity of insulin target cells toward insulin, finally forming a vicious circle and aggravating insulin resistance. Moreover, a network framed by PPARγ, NF-κB, and PTP1B signaling pathways crossing with the JNK signaling pathway plays a crucial role in regulating insulin resistance [28].

We assumed that a better understanding of the JNK signaling pathway and its relationship with PPARγ, NF-κB, PTP1B signaling pathways are necessary for a new drug targeting the treatment of obesity and mood disorders [28].

SORBS2: The role of SORBS2 gene in obesity and mood disorders has been discovered recently by different genome-wide methylation studies [37]. This gene located on the 4q35. 1 encodes the Arg protein tyrosine kinase binding protein 2 (ArgBP2). SORBS2 is an RNA-binding protein, which is involved in the regulation of RNA metabolism [38]SORBS2 is involved in several biological pathways. Sorbin, the product of SORBS2, is an ArgBP2 protein and SH3 domain-containing protein 2 and might be involved in insulin-mediated translocation of GLUT4 and thereby might affect energy storage [39]. Previous research has highlighted the role of this functional protein in disease states [40][41][42][43]. Downregulation of this gene was reported to be associated with mood disorders [44]. Linear regression analyses revealed a strong association of methylation with BMI for SORBS2 in abdominal omental visceral adipose tissue [45]. There is enough data to provide functional evidence that promoter methylation in SORBS2 directly influences gene activity and thus contributes to the abiogenesis. We suggest that SORBS2 is related to obesity through the innate immunity and inflammation response by the Notch signaling pathway that plays a major role in adipogenic differentiation [46]. Increased Notch signaling in mice blocked the expansion of white adipose tissue, ectopic fat accumulation, and insulin resistance [47].

The genetic deletion of Sorbin in mice leads to mood disorders by a reduction in the average number of spines per dendrite [41]. Additionally, to the grapevine, SORBS2 is related to mood disorders through two different pathways; actin-related proteins and the Notch signaling pathway [48][49]. Notch signaling is important in regulating neural cell proliferation, differentiation, and neural cellular growth, and is considered as a contributor in adaptive and innate immune responses. Active Notch signaling has been observed under a variety of inflammatory conditions such as atherosclerosis [47][50]. Interestingly, prototypical proinflammatory cytokines positively regulate Notch signaling and its target gene expression. For example, TNF induces expression of Notch1, Notch4 [51]. In addition, IL-1β induces Notch target genes, and Interferon-γ (IFNγ) functions as a negative regulator of Notch pathway activation [52].

BDNF: This gene is located in the 11p14.1 and encodes a member of the nerve growth factor family of proteins [53]. Alternative splicing results in multiple transcripts, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature protein. Binding of this protein to its cognate receptor promotes neuronal survival in the adult brain. BDNF gene structure is complex, regulated by nine functional promoters. Each promoter regulates the expression of this gene [54]BDNF encompasses several biological pathways and has a complex regulation; the exact roles of BDNF and its transcripts are not fully understood. BDNF insufficiency or missense mutations in its receptor, TrkB, are associated with weight gain and obesity in humans and mouse models [55][56]. In line with these observations, both exogenous BDNF administration and BDNF gene transfer in mouse model support the concept of the BDNF deficit in the brain induces a metabotropic impairment leading to obesity. Essentially, it has been established that the hypothalamic reduction of BDNF modulates energy homeostasis affecting food intake and promoting an anorectic signal [57].

There are several pieces of evidence about the role of BDNF in brain function and mood disorders [58][59][60]. Previous studies indicated that the positive correlation between brain and circulating BDNF suggests that BDNF levels in the blood reflect the levels occurring in the central nervous system. Thus, circulating BDNF has been proposed as a potential biomarker for neuropsychiatric disorders and neurodegenerative diseases [61][62][63][64][65][66].

BDNF is one of the major neurotrophic factors, plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression and plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Recent documents demonstrated that the expression of BDNF is decreased in depressed patients [67]. BDNF has a multifaceted role from its neurotrophic activity to inflammation, metabolism, and cardiovascular diseases [68][69][70].

Methylation of the BDNF gene was analyzed at CpG sites in upstream of exon I. It is also possible that the hypomethylation promotor is located in exon I, which could cause altered BDNF expression, leading to abnormal eating behaviors [71][72]. Gardner et al. displayed different methylation in the promoter of BDNF related to obesity [71]. Interestingly, three of the obesity-associated CpGs were located within two of the numerous promoters of BDNF, and differential BDNF transcripts are expressed at different time points and in different cellular compartments [73][74]. Carriers of the risk allele at rs10767664 had higher methylation in the pII promoter of BDNF, and lower methylation in the pVI promoter of BDNF [75]. Januar et al. have revealed that late-life depression is associated with elevated BDNF methylation of specific CpG sites within promoters I and IV, with all associations remaining after adjustment for a range of covariates [76].

Furthermore, recent studies reported an increased BDNF methylation is associated with depression in animal models [77] and in humans [78]. Decreased BDNF may relate to the reduced function of the BDNF gene in promoting neural growth and repair in depression. Thus, among depressive patients, those with a higher BDNF methylation status are at a greater risk of suicidal behavior [79]. Hypermethylation in Exon I, in the promoter region, reduced BDNF levels in the plasma and post-mortem hippocampus of depressed individuals [80][81][82][83]. Another post-stroke cohort indicated that higher BDNF promoter methylation status was independently associated with depressive symptoms over one year after the onset of stroke, although not associated with baseline depressive symptom severity [79][84][85]. The methylation state of CpG sites within mouse promoter/exon IV is correlated with the expression of BDNF in the developing mouse forebrain, and similar associations were found with chronic depression, and these effects were not driven by antidepressant treatment [61]. For example, Jin et al. using the Sequenom Mass Array platform, demonstrated in mice model that fluoxetine can downregulate the expression of BDNF by the methylation of 11 CpG sites in promoter IV [86].

Strangely, BDNF has leading biological roles in inflammation and apoptosis; consequently, it is a crucial neurotrophic factor for preserving normal nervous system function. Moreover, BDNF is an associated member of the neurotrophic factor family that is mainly secreted by neuron or glial cells [87].

Sources of chronic inflammation or non-resolving inflammation may originate from either pathophysiological (e.g., inflammatory diseases, immune-based disorders, T cell dysfunction) or non-pathological conditions, including aging and obesity. Interestingly, BDNF has main biological roles in inflammation and apoptosis; thus, it is a crucial neurotrophic factor for preserving normal nervous system function [87].

Additionally, BDNF has a multifaceted role from its neurotrophic activity to inflammation, metabolism, and cardiovascular diseases. BDNF is considered as a potential modulator/mediator with anti-inflammatory effects [81].

BDNF-related neuroprotective effects are elicited by activation of extracellular signal-related kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-signaling pathways. Production of inflammatory cytokines can regulate by complex signaling pathways, especially nuclear factor-κb (NF-κB) and inflammatory response signal pathway (BDNF-TrkB-MEK-ERK-NF-κB pathway) [88][89][90].

3. Conclusions

While mechanisms linking both obesity and mood disorders to epigenetic response are still unknown, it is well-known that chronic inflammation induces a novel epigenetic program. As the results of gene enrichment pathways analysis exhibited that TAPBP, BDNF, and SRBP2 are related together by inflammatory pathways, we hypothesis that hypermethylation in these genes might play a crucial role in the co-occurrence of obesity and mood disorders due to the inflammation process. Our results shed light on our understanding of such associations. Future studies should focus on the molecular pathophysiology of these disorders in the hope of opening new approaches for target treatment.


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