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Review

The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder

by
Jingxian Cao
1,
Philip Gorwood
1,2,*,
Nicolas Ramoz
1,2,† and
Odile Viltart
1,3,†
1
Institute of Psychiatry and Neuroscience of Paris (IPNP), Université Paris Cité, INSERM UMR-S 1266, F-75014 Paris, France
2
GHU Paris Psychiatrie et Neurosciences, CMME, Hôpital Sainte Anne, F-75014 Paris, France
3
SCALab Laboratory, PsySEF Faculty, Université de Lille, UMR CNRS 9193, F-59650 Villeneuve d’Ascq, France
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Nutrients 2024, 16(16), 2617; https://doi.org/10.3390/nu16162617
Submission received: 12 June 2024 / Revised: 26 July 2024 / Accepted: 4 August 2024 / Published: 8 August 2024
(This article belongs to the Section Nutrition and Public Health)
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Abstract

:
Neurotrophic factors play pivotal roles in shaping brain development and function, with brain-derived neurotrophic factor (BDNF) emerging as a key regulator in various physiological processes. This review explores the intricate relationship between BDNF and anorexia nervosa (AN), a complex psychiatric disorder characterized by disordered eating behaviors and severe medical consequences. Beginning with an overview of BDNF’s fundamental functions in neurodevelopment and synaptic plasticity, the review delves into recent clinical and preclinical evidence implicating BDNF in the pathophysiology of AN. Specifically, it examines the impact of BDNF polymorphisms, such as the Val66Met variant, on AN susceptibility, prognosis, and treatment response. Furthermore, the review discusses the interplay between BDNF and stress-related mood disorders, shedding light on the mechanisms underlying AN vulnerability to stress events. Additionally, it explores the involvement of BDNF in metabolic regulation, highlighting its potential implications for understanding the metabolic disturbances observed in AN. Through a comprehensive analysis of clinical data and animal studies, the review elucidates the nuanced role of BDNF in AN etiology and prognosis, emphasizing its potential as a diagnostic and prognostic biomarker. Finally, the review discusses limitations and future directions in BDNF research, underscoring the need for further investigations to elucidate the complex interplay between BDNF signaling and AN pathology.

1. AN: A Metabo-Psychiatric Disorder with Complex Etiology

Human brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has long been recognized for its regulatory roles in crucial functions, such as neuron survival, differentiation, and specification. In the mature nervous system, BDNF modulates synaptic transmission and axonal morphology, ultimately affecting behavior, learning, memory and, in particular, feeding behavior [1]. Alterations in BDNF pathways have been described in several psychiatric disorders. In recent decades, its intricate involvement has extended to eating disorders, with compelling evidence linking BDNF to several disorders including anorexia nervosa (AN) [2].
After a short description of the role and functions of BDNF, our review will update recent clinical and preclinical data showing how BDNF can be a key biomarker in the physiopathology of AN.
AN is a complex psychiatric disorder characterized by voluntary dietary limitation and excessive physical activity due to the patient’s fear of weight gain and desire to lose body weight although underweight, according to DSM-5 [3]. AN encompasses two main subtypes: the restrictive type (AN-R), characterized by severe food restriction, and the binge–purge type (AN-BP), marked by episodes of binge eating followed by purging behaviors [4]. The female-to-male ratio of AN is around 10/1 to 15/1, young women being the most vulnerable [5,6]. Anorexia nervosa presents a substantial threat, bearing the highest mortality rate among psychiatric disorders. Patients often persist in food restriction despite reaching dangerously low body mass index (BMI), risking severe malnutrition and medical complications, including organ failure [7,8,9]. In addition, the high comorbidity with numerous psychiatric disorders such as major depressive disorder (MDD) and anxiety disorder (AD) highly increases the risk of patients to commit suicide [10,11,12]. Indeed, AN is notoriously difficult to treat, with a complex chronicity and a relapse rate of up to 50% in the first year, and with more than 20% of patients eventually experiencing recurrent patterns of remission and relapse [6,13,14,15]. Currently, the only proven treatment for AN remains re-feeding strategies combined with psychotherapy, as there are still no effective pharmacological treatments [16].
Recently, AN has been reconceptualized as a metabo-psychiatric disorder according to a genome-wide association study (GWAS), which provides evidence that various genetic factors are involved in the etiology of AN, related to both neuro-psychiatric factors and to anthropometric and metabolic pathways [17]. In support of this notion, substantial evidence found in familial associations studies highlights the high heritability of AN (up to 70%) [18,19,20]. Furthermore, a large-scale GWAS identified eight risk loci associated with AN [17]. Case-control studies have also pointed out other genetic risk factors for AN, such as 5-hydroxytryptamine receptor 2A (HTR2A), serotonin transporter (5-HTT), estrogen receptor 1 (ESR1), or BDNF [21,22,23]. More particularly for the latter, the rs6265 polymorphism (or Val66Met) is clearly associated with AN symptomatology [24,25], while BDNF has been shown to be closely involved in both mood and metabolic regulation, the two main physiological aspects of AN (Figure 1).

2. Brain-Derived Neurotrophic Factor and Val66Met Polymorphism

The human BDNF gene is located on chromosome 11, region p13–14 and spans approximately 70 kb [26]. The BDNF gene encodes a neuropeptide that is first produced in neurons as pro-BDNF, then cleaved to mature BDNF (mBDNF), and finally secreted into the synapse to bind to the tropomyosin receptor kinase B (TrkB) (NTRK2/TrkB gene) on the postsynaptic membrane [27,28,29,30]. BDNF belongs to the neurotrophin family [31]. Its signaling through the TrkB receptor is essential for neuronal survival, neuronal development, synaptogenesis, and long-term potentiation [32,33,34,35]. Pro-BDNF has a different signaling profile from BDNF, as it can bind directly to the p75 neurotrophin receptor (p75NTR), which promotes neuronal apoptosis and synaptic pruning [36,37,38]. The BDNF gene is essential for early survival, as total knockout of the BDNF gene in mice results in severe malformation and death in the first postnatal days [39] (Figure 2).
Several polymorphisms (SNP) have been identified in the human BDNF gene, of which rs6265 (Val66Met) is one of the most studied. Val66Met is a functional variant of human BDNF in which the 66th amino acid, a valine, is substituted by a methionine [40].
The Val66Met polymorphism in the BDNF gene results in significant changes in BDNF signaling, affecting multiple aspects of neuronal function and behavior. Mechanistically, Met carriers exhibit attenuated BDNF signaling due to impaired epigenetic regulation, disrupted dendritic trafficking of BDNF mRNA, and reduced availability of mature BDNF and its secretion [41,42,43,44]. These alterations result in lower basal BDNF levels and TrkB signaling, impaired neurogenesis, and cognitive deficits observed in both animal models and human studies [41,45,46,47,48,49] (Figure 3).

3. BDNF and AN: Clinical Data

The association between the Val66Met polymorphism and AN has been investigated in various studies, with inconsistent findings. Indeed, a meta-analysis encompassing nine studies and involving a total of 2767 cases and 3322 controls found no clear association between the Val66Met polymorphism and the onset of AN [50], while certain demographic groups, such as individuals of Spanish descent, have exhibited an association between the Met variant and restrictive AN, along with a correlation between the number of Met alleles and the minimum body mass index (BMI). Recently, a genome-wide association study (GWAS) found no significant associations between the BDNF gene and AN [17].
These inconsistencies reflect differences between populations and methods. Factors such as sample size, patient demographics, and study design may indeed contribute to the variability of results. Nevertheless, recent studies have suggested that the Met variant may increase the risk of developing AN, particularly in individuals with comorbid borderline personality disorder [51]. The Val66Met polymorphism was also associated with an increased reward value attributed to images depicting starvation [25] in patients with restrictive AN, supporting several psychological symptoms or phenotypes associated with genetic of BDNF (Figure 3). For AN-BP, studies have not found significant associations with the Val66Met polymorphism [52]. Other BDNF haplotypes have been implicated in AN and related eating disorders, such as bulimia nervosa [53,54]. However, further research is needed to elucidate the precise role of BDNF and its receptor genes in the etiology and symptomatology of AN.
Conflicting results were also observed for circulating BDNF levels. While some reported decreased BDNF levels in patients with AN [50,55], other studies report higher plasmatic BDNF levels in patients with AN, particularly those carrying the Met variant [24,54]. The increase in circulating BDNF remained at supranormal levels up to 2.5 years after first hospitalization [56]. Despite some discrepancies concerning the variation in BNDF, a certain number of studies have linked the variation in BDNF signaling and specific symptoms of AN. For instance, reduced levels of circulating BDNF were observed in patients with AN with very low body mass index upon admission, while weight rehabilitation subsequently restored BDNF plasma levels [55]. Though BDNF levels in the cortex or serum have been found to positively correlate with cognitive flexibility in various animal models and human subjects [57,58,59], there is no correlation in patients with AN between serum BDNF levels and impaired cognitive flexibility [60]. Thus, limited evidence exists regarding the relationship between the Val66Met polymorphism and anthropometric and psychological parameters in AN patients [61].
These data point out a complex and nuanced relationship between the expression of BDNF and AN pathology, contingent upon the presence or absence of the variant, the subtype of AN, and the stage of the disorder. A better investigation of this biomarker could unveil significant implications for comprehending the psychiatric manifestations linked to the disorder [61].

4. BDNF and AN: Inputs from Animal Models

While no animal model can fully capture all aspects of AN, due to its complexity both at metabolic and psychological levels, the rodent models currently used in research mimic specific facets of the disorder. These models serve to simulate certain behaviors or metabolic conditions observed in AN rather than replicating the disorder in its entirety. For instance, short-term food restriction models, such as the activity-based anorexia (ABA) model, aim to replicate aspects of the restrictive eating behavior seen in AN [62]. Meanwhile, chronic food restriction models, such as the food restriction with running wheels (FRW) model, focus on mimicking the long-term consequences of caloric deprivation often associated with AN [63].
Examining the BDNF expression profile in brain regions of rodents subjected to the ABA model reveals interesting dynamics (Table 1). During scheduled feeding in the ABA model, rodents show increased BDNF levels in the hippocampus but decreased levels in the medial prefrontal cortex (mPFC), contributing to anorexia-like behaviors via alterations in the brain’s reward circuitry [64,65]. In an ABA experiment, it was demonstrated that the use of a running wheel increases BDNF expression in the ventral tegmental area (VTA), while BDNF levels in the hippocampus or nucleus accumbens (NAc) were not affected by either wheel running or food restriction [65]. Furthermore, a recent study highlighted a persistent downregulation of BDNF signaling in the amygdala of ABA-exposed rodents, despite an increase in mature BDNF protein levels, underscoring the complex neurobiological alterations induced by food restriction [66]. The mPFC has a critical role in executive functions such as cognitive control and decision making, the hippocampus is more involved in memory formation and emotional regulation, while the VTA is a core structure in reward processing (Figure 4). Interestingly, these three structures were implicated in AN onset [67,68,69,70,71,72]. Alterations of BDNF expression within these brain regions in response to food restriction provide compelling evidence supporting the hypothesis that AN initiation may involve aberrant BDNF signaling.
Table 1. Regional modification of BDNF under metabolic or psychological stress.
Table 1. Regional modification of BDNF under metabolic or psychological stress.
TissueGeneCalory Restrictions (Chronic)Fasting (Acute)Physical ActivitiesHigh Fat Diet/ObesityChronic StressAcute Stress
ChangeSpecies/SexChangeSpecies/SexChangeSpecies/SexChangeSpecies/SexChangeSpecies/SexChangeSpecies/Sex
PFCBDNFNs ProtRat ♂ [73,74] ↑ mRNAMice ♂ [75]↓ ProtRats ♂ [76]↓ mRNARat ♂ [77]↓ mRNARat ♂ [77]
↑ ProtRat ♀♂ [78,79]↑ ProtRat ♂ [80]
HippocampusBDNF↑ ProtRat ♀♂ [73,78,79]↓ Cell NbMice ♂ [81] Ns mRNAMice [75]↓ ProtRats ♂ [76]
↓ Cell NbRat ♂ [82]↑ ProtMice ♂ [83] ↓ mRNAMice ♂ [84]
TrkBNs Cell NbRat ♂ [82] ↓ mRNAMice, ♂ [84] Ns ProtRat ♂ [80]
HypothalamusBDNF ↓ mRNAMice ♂, Rat ♀♂ [84,85]↑ mRNA, protRat ♂ [86]↑ mRNARat ♂ [87]
TrkB Ns mRNAMice ♂ [84]
DSBDNF ↑ ProtMice ♂ [88] ↑ mRNA,protMice ♂ [89]
NAcBDNFNs ProtRat ♂ [74] ↑ mRNAHuman ♀♂ [90]↑ ProtRat ♂ [91]
TrkB ↑ ProtRat ♂ [91]
VTABDNFNs mRNA, protRat ♂ [74] ↑ ProtRat ♂ [91]
TrkB↓ ProtRat ♂ [74] ↑ ProtRat ♂ [91]
AmygdalaBDNF↑ ProtRat ♂ [73]↓ mRNARats ♀ (ABA) [66] ↓ mRNA, protRat ♂ [92]
Serum/PlasmaBDNFNs ProtRat ♂ [79] ↑ ProtHuman ♂ [93]↓ ProtHuman ♀ [94]↑ ProtHuman ♂ [95] ↑ ProtHuman ♂ [95]
Ns: no significant change. ↑: increases. ↓: decreases. Prot: protein. Nb: number. ♂: male. ♀: female.
Nutrients 16 02617 g004
Figure 4. Brain circuits implicated in anorexia symptomatology. PFC: prefrontal cortex. DS: dorsal striatum. NAc: nucleus accumbens. AMY: amygdala. HIP: hippocampus. VTA: ventral tegmental area. HPT: hypothalamus [96,97,98].
Figure 4. Brain circuits implicated in anorexia symptomatology. PFC: prefrontal cortex. DS: dorsal striatum. NAc: nucleus accumbens. AMY: amygdala. HIP: hippocampus. VTA: ventral tegmental area. HPT: hypothalamus [96,97,98].
Nutrients 16 02617 g004
In the ABA model, vulnerable mice exhibit maladaptive behaviors under food restriction, including increased running activities, reduced food intake, and excessive weight loss, resulting in an anorexia-like phenotype [99]. The Val66Met polymorphism does not appear to influence the manifestation of vulnerability in ABA rats [100]. Although knock-in mice with the Met variant display higher baseline anxiety, both WT and Met mice exhibit similar levels of anxiety under the ABA protocol [101]. However, in a chronic food restriction protocol, Met mice exposed to adolescent social stress show increased metabolic vulnerability and higher anxiety levels compared to WT littermates, whereas exposure to social stress during adulthood does not result in a significant difference [102], supporting the idea that the Val66Met polymorphism may create a genetic predisposition, which, when combined with exposure to juvenile social stress and calories restriction, increases the likelihood of the onset of anorexia-like behaviors. This elucidates the intricate interplay between genetic predisposition and environmental stressors, underscoring the complexity of AN etiology and may provide valuable insights for the development of targeted interventions or therapeutic strategies.

5. BDNF and Stress-Related Mood Disorders

It is important to recognize that AN is closely associated with stress, as stress can increase vulnerability to the disorder [103,104].
In the context of stress-related mood disorders, such as depression and anxiety, environmental stress significantly affects BDNF expression in various brain regions (Table 1). Studies in rodent models indicate that exposure to environmental stressors decreases BDNF mRNA expression in key brain regions implicated in mood regulation, including the hippocampus, prefrontal cortex, and amygdala [92,105,106,107]. The downregulation of BDNF mRNA in these regions is associated with the manifestation of depressive-like behaviors and increased susceptibility to stress-induced mood disorders, including decreased social interaction, heightened behavioral despair, dysphoria, and elevated anxiety levels [105,106,107].
Interestingly, the effects of BDNF on mood regulation vary depending on the brain region. Indeed, BDNF expression in the hippocampus is typically associated with an antidepressant effect. On the contrary, BDNF signaling in the dopamine mesocorticolimbic circuit appears to have a depressive effect, as both BDNF infusion and TrkB overexpression induce shorter latency to immobility in forced swimming tests, while BDNF KO or a reduction in BDNF signaling, via a dominant negative receptor, has opposite effects [89,108]. Increasing BDNF levels in the NAc, VTA, and dorsal striatum (DS)—a critical region for cognitive flexibility [90] (Figure 4)—contributes to the development of susceptibility to depressive-like phenotypes under conditions of repeated aggression stress [109,110,111] (Table 1). Conversely, a reduction in BDNF levels within these areas has been associated with an antidepressant effect [112]. In humans, post-mortem studies of individuals with major depressive disorder who died by suicide have further highlighted region-specific alterations in BDNF expression, with reduced hippocampal BDNF but increased BDNF levels in the NAc [111,113], suggesting a region-specific dysregulation of BDNF expression in relation to mood disorder. Such results mirror observations from animal studies and offer valuable insights into the nuanced role of BDNF signaling across various brain circuits.
The Val66Met polymorphism of the BDNF gene has been implicated in increasing genetic vulnerability to mood disorders in response to environmental stimuli. In adolescent social stressed mice, the knock-in of the human Val66Met variant increases the likelihood and severity of anorexic behavior induced by caloric restriction [102]. In addition, Met-carrying mice tend to exhibit higher adrenal responses and experience more behavioral impacts after stress exposure, including decreased social interaction, impaired novelty exploration, and higher anxiety levels [114] (Figure 3).
In human studies, the Met variant interacts with stressful life events and childhood adversity, increasing the risk of developing depression-like symptoms, neuroticism, subclinical psychotic experiences, as well as suicidal behaviors [115,116,117,118]. These interactions are often associated with corresponding alterations in brain regions such as the hippocampus and lateral prefrontal cortex, as revealed by structural magnetic resonance imaging (MRI) [119]. However, conflicting findings have also been reported, with some studies suggesting that Met carriers show reduced vulnerability to high stress and reduced sensitivity to the benefits of stress reduction [120,121]. Specifically, male Met carriers have lower cortisol responses under stress, whereas female Met carriers have higher cortisol responses under stress [122,123]. These findings highlight the complex interplay between genetic factors, stress exposure, and neurobiological mechanisms in shaping vulnerability to mood disorders. Such intricate relationships may have implications for understanding the pathophysiology of AN, particularly given its significant prevalence among females.
Collectively, these findings suggest that BDNF plays a critical role in determining vulnerability/resilience to environmental stress, with specific effects observed in different brain regions. Understanding the nuanced interactions between BDNF and environmental stressors may provide valuable insights into the pathophysiology of stress-related mood disorders, particularly associated with AN, and inform the development of targeted therapeutic interventions.

6. BDNF and Metabolism

The metabolic consequences of chronic starvation in individuals with AN have been well established through metabolomic studies, shedding light on the intricate relationship between metabolic dysregulation and the maintenance of the disorder [124]. Accordingly, further investigation into the metabolic role of BDNF may provide valuable insights into its potential as a biomarker for AN.
In addition to its classical roles in neuronal protection, synaptogenesis, and mood regulation, recent studies have revealed a central involvement of BDNF in metabolic regulation. Animal studies have shown that BDNF exerts its metabolic effects via hypothalamic signaling pathways. For example, targeted deletion of the BDNF gene in the paraventricular nucleus (PVN), the principal endocrinal control center in metabolic homeostasis [125], leads to hyperphagia and an obese phenotype in animals, accompanied by decreased locomotor activity and reduced thermogenesis [126]. Conversely, activation of the BDNF gene or central administration of the BDNF protein in the PVN produces opposite effects, suggesting a direct influence of PVN BDNF on hypothalamic neurons and subsequent metabolic processes [127,128,129].
The arcuate nucleus (ARC) in the hypothalamus is primarily composed of two groups of neurons: pro-opiomelanocortin (POMC) neurons and agouti-related peptide (AgRP)/neuropeptide Y (NPY) neurons [125]. POMC neurons are known to promote satiety and reduce food intake, while AgRP/NPY neurons stimulate appetite and increase food consumption [125]. Both types of neurons project to the paraventricular nucleus (PVN) and other hypothalamic regions, playing crucial roles in the regulation of energy balance and food ingestion [125]. A small fraction of POMC and AgRP/NPY neurons in the ARC were found to express the TrkB receptor [130]. Suppression of BDNF mRNA in the ARC leads to severe hyperphagic obesity, accompanied by decreased axonal projections from the ARC to the PVN, further demonstrating the importance of BDNF signaling in central metabolic regulation [130].
Furthermore, the effects of BDNF on metabolism extend beyond the confines of the brain, as peripheral tissues also contribute significantly to metabolic regulation and interact with central BDNF signaling. Peripheral expression of the BDNF gene is widespread in various tissues, including skeletal and smooth muscle, adipose tissue, liver, spleen, and others [131,132,133,134,135,136]. These peripheral sources of BDNF modulate metabolic processes in a complex manner.
For example, in the liver, BDNF administration activates catabolic pathways, including fatty acid oxidation and glycogen synthesis [137,138,139]. Adipose tissue-derived BDNF also plays a crucial role in metabolism by regulating local processes in white adipose tissue, such as sympathetic innervation, mitochondrial function, and susceptibility to obesity-related challenges [136,140,141]. Similarly, skeletal muscles secrete BDNF in response to contraction and fasting, thereby contributing to glucose and lipid metabolism [142,143,144,145,146].
Concerning the Val66Met polymorphism, numerous studies demonstrated its involvement in body weight regulation, with distinct associations in both animal and human studies. Animal models, in particular homozygous knock-in BDNF met/met mice, showed a phenotype characterized by hyperphagia, obesity, and altered inflammatory profiles in addition to reduced hypothalamic BDNF expression [48,147]. Conversely, human genotype–phenotype association studies suggest that Met-Met individuals tend to have lower body mass index compared to Val-Met or Val-Val individuals [148,149,150,151,152,153]. Furthermore, while the Met variant is not associated with serum BDNF levels, it correlates with reduced BDNF gene expression in muscle tissue, as demonstrated by human biopsy analysis [154,155,156] (Figure 3).
These findings underscore the challenge of translating observations from human genetic variants to animal models and highlight potential differences in the regulation of BDNF signaling between species. Notably, while AN primarily involves metabolic challenges due to long-term food restriction and low body weight, research on the association of the Val66Met polymorphism with metabolism has primarily focused on obesity, with limited exploration in the context of chronic calorie restriction.

7. Discussion

7.1. Role of BDNF in AN Etiology and Prognosis

Despite the limited direct evidence linking the Met variant to AN, current evidence on interrelated BDNF polymorphisms and altered BDNF levels suggests that BDNF is a plausible candidate for the etiology of AN. The paradoxical circulating BDNF levels in AN patients underscore the complexity of this disorder and highlight the challenges in under-standing its underlying mechanisms.
It is important to note that AN encompasses two primary subtypes: restrictive and binge–purge. These subtypes can exhibit different clinical and biological characteristics, potentially leading to varying BDNF levels and responses. Research suggests that the AN-R may have different metabolic and neurobiological profiles compared to AN-BP [154,155]. Therefore, studies examining AN as a single category may yield distorted results due to this heterogeneity. Recognizing these differences is crucial for accurately interpreting findings and developing subtype-specific biomarkers and treatments.
While animal studies clearly demonstrate the anorexigenic effects of BDNF, extrapolating its role and changes in plasma levels in patients is challenging. Several findings indicate that BDNF levels are not only influenced by acute nutritional status but may also have long-term alterations in individuals with a history of AN [56,60]. Hypothetically, persistent changes in BDNF signaling post-BMI recovery could underlie an increased risk of relapse, emphasizing the importance of considering long-term effects in the study of BDNF and AN. This aspect warrants further investigation to enhance our understanding of the relationship between BDNF and nutritional status and to explore the potential of BDNF as a biomarker for the prognosis of AN.

7.2. Exploring the Biomarker Potential of Circulating BDNF

Numerous studies have investigated the potential of circulating BDNF as a biomarker for various diseases. Subsequently, circulating BDNF levels have been found to correspond to psychiatric status, with interactions with genotype [108,112,156]. Changes in plasma BDNF levels vary, showing either increases or decreases in different psychiatric disorders [157,158,159,160,161]. However, as mentioned above, the results in individuals with AN are paradoxical.
Circulating BDNF may also serve as a marker for the psychiatric prognostic status of AN patients, given the propensity of AN patients to have psychiatric symptoms that implicate BDNF. For example, AN patients often exhibit reward abnormalities, and BDNF has been implicated in reward dependence [162,163]. The prevalence of childhood adversity and stressful life events in AN patient further supports the role of BDNF as an intermediary factor in the relationship between life stress and psychiatric disorders [108,112,156,164].

7.3. Metabolic Implications and Sexual Dimorphism

Exploration of the relationship between circulating BDNF and metabolic status has predominantly focused on obesity and responses to dietary interventions such as chronic calorie restriction and intermittent fasting, with somewhat inconclusive results [144,165,166]. Ethical considerations limit studies into the effects of long-term food restriction on circulating BDNF levels in healthy subjects. Nevertheless, existing studies suggest that chronic calorie-restricted diets may increase serum BDNF levels in overweight populations and negatively correlate with body weight [167].
AN has a strong female sexual dimorphism that cannot yet be explained by sociological factors. Female rats experiencing maternal separation show decreased anxiety behavior under the ABA model, suggesting a unique interaction between stress and dieting that is also highly sexually dimorphic [168]. The effects of BDNF on psychiatric traits and metabolism often also exhibit sexual polymorphism, highlighting additional features shared with the etiology of AN and further strengthening its potential implications [142,169,170,171].
Recent years have seen an increasing recognition of AN in males, who now represent a significant subset of those affected by the disorder. While men with AN often present with similar core symptoms as women, such as restrictive eating and intense fear of gaining weight, they may place more emphasis on muscularity and leanness rather than thinness alone [172,173]. This gender-specific focus on body image can lead to behaviors like excessive exercise, which may sometimes be overlooked in diagnostic assessments [172,173]. Male patients with anorexia nervosa often experience more significant weight loss prior to treatment and require longer durations of hospitalization for weight restoration compared to their female counterparts [174]. Psychiatric comorbidities in males with AN, such as lower rates of specific phobia, also differ from those typically observed in females [175], potentially influencing treatment outcomes.
Given these differences, there is a critical need for gender-specific research on BDNF in AN. Understanding the role of BDNF in male AN patients could lead to the development of more effective, personalized treatment strategies.

7.4. The Paradox of Physical Activity

Physical activity plays a significant role in the regulation of BDNF levels, which is particularly relevant in the context of AN. Exercise is generally associated with beneficial effects on mental health, and improved cognitive function and mood [176], which are typically associated with increased BDNF levels [177,178]. However, in patients with AN, this relationship appears to be more complex. Hyperactivity, which is a common feature of AN, may be driven by abnormal BDNF signaling pathways, leading to a paradoxical effect where increased physical activity exacerbates the disorder rather than alleviating it.
The interaction between hyperactivity and BDNF in AN suggests that while exercise might have neuroprotective effects under normal circumstances, the altered BDNF expression observed in AN patients could contribute to the maintenance of pathological behaviors. This complex interplay underscores the need for further research to disentangle these relationships and to develop targeted interventions that address both the physiological and psychological aspects of AN.

7.5. Limitations and Future Directions

The paradoxical results observed in circulating BDNF levels in AN patients may also be due to the multiple origins of the molecule. BDNF can cross the blood–brain barrier [179]. However, there is currently no evidence that circulating BDNF corresponds to cerebral BDNF [180,181]. The heterogeneity of cerebral BDNF also call into question the representativeness of circulating BDNF, as it cannot profile the details in different brain regions [108]. Furthermore, due to the different sources of BDNF in peripheral organs, circulating BDNF is unlikely to accurately profile the BDNF levels of a specific organ. Furthermore, plasmatic BDNF has a distinct circadian rhythm, especially in women, which may contribute to the inconsistent results observed in different studies [182].
In conclusion, although research into the role of BDNF as a biomarker for psychiatric disorders and metabolic disorders has been fruitful, the current limitations make it difficult to definitively assert its utility as a diagnostic or prognostic biomarker for AN. Further investigations should include larger patient cohorts with minimized confounding factors, with the aim of establishing a precise correlation between circulating BDNF and BDNF levels in different brain regions and peripheral organs. The use of AN-like animal models may provide valuable insights into the origin and dynamics of circulating BDNF.

Author Contributions

Conceptualization, J.C., O.V. and N.R.; writing—original draft preparation, J.C., O.V. and N.R.; writing—review and editing, J.C., P.G., N.R. and O.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Vanevski, F.; Xu, B. Molecular and Neural Bases Underlying Roles of BDNF in the Control of Body Weight. Front. Neurosci. 2013, 7, 43608. [Google Scholar] [CrossRef] [PubMed]
  2. Trinh, S.; Keller, L.; Herpertz-Dahlmann, B.; Seitz, J. The Role of the Brain-Derived Neurotrophic Factor (BDNF) in Anorexia Nervosa. Psychoneuroendocrinology 2023, 151, 106069. [Google Scholar] [CrossRef] [PubMed]
  3. Diagnostic and Statistical Manual of Mental Disorders. Available online: https://dsm.psychiatryonline.org/doi/book/10.1176/appi.books.9780890425596 (accessed on 15 November 2022).
  4. DaCosta, M.; Halmi, K.A. Classifications of Anorexia Nervosa: Question of Subtypes. Int. J. Eat. Disord. 1992, 11, 305–313. [Google Scholar] [CrossRef]
  5. Micali, N.; Hagberg, K.W.; Petersen, I.; Treasure, J.L. The Incidence of Eating Disorders in the UK in 2000–2009: Findings from the General Practice Research Database. BMJ Open 2013, 3, e002646. [Google Scholar] [CrossRef] [PubMed]
  6. Treasure, J.; Stein, D.; Maguire, S. Has the Time Come for a Staging Model to Map the Course of Eating Disorders from High Risk to Severe Enduring Illness? An Examination of the Evidence. Early Interv. Psychiatry 2015, 9, 173–184. [Google Scholar] [CrossRef] [PubMed]
  7. Arcelus, J.; Mitchell, A.J.; Wales, J.; Nielsen, S. Mortality Rates in Patients With Anorexia Nervosa and Other Eating Disorders: A Meta-Analysis of 36 Studies. Arch. Gen. Psychiatry 2011, 68, 724–731. [Google Scholar] [CrossRef]
  8. Westmoreland, P.; Krantz, M.J.; Mehler, P.S. Medical Complications of Anorexia Nervosa and Bulimia. Am. J. Med. 2016, 129, 30–37. [Google Scholar] [CrossRef] [PubMed]
  9. Rosen, E.; Bakshi, N.; Watters, A.; Rosen, H.R.; Mehler, P.S. Hepatic Complications of Anorexia Nervosa. Dig. Dis. Sci. 2017, 62, 2977–2981. [Google Scholar] [CrossRef]
  10. Fernandez-Aranda, F.; Pinheiro, A.P.; Tozzi, F.; Thornton, L.M.; Fichter, M.M.; Halmi, K.A.; Kaplan, A.S.; Klump, K.L.; Strober, M.; Woodside, D.B.; et al. Symptom Profile of Major Depressive Disorder in Women with Eating Disorders. Aust. N. Z. J. Psychiatry 2007, 41, 24–31. [Google Scholar] [CrossRef]
  11. Swinbourne, J.M.; Touyz, S.W. The Co-Morbidity of Eating Disorders and Anxiety Disorders: A Review. Eur. Eat. Disord. Rev. J. Eat. Disord. Assoc. 2007, 15, 253–274. [Google Scholar] [CrossRef]
  12. Pompili, M.; Mancinelli, I.; Girardi, P.; Ruberto, A.; Tatarelli, R. Suicide in Anorexia Nervosa: A Meta-analysis. Int. J. Eat. Disord. 2004, 36, 99–103. [Google Scholar] [CrossRef] [PubMed]
  13. Carter, J.C.; Blackmore, E.; Sutandar-Pinnock, K.; Woodside, D.B. Relapse in Anorexia Nervosa: A Survival Analysis. Psychol. Med. 2004, 34, 671–679. [Google Scholar] [CrossRef] [PubMed]
  14. Steinhausen, H.-C. Outcome of Eating Disorders. Child Adolesc. Psychiatr. Clin. N. Am. 2009, 18, 225–242. [Google Scholar] [CrossRef] [PubMed]
  15. Duriez, P.; Maatoug, R.; Verbe, J. Failure of Electroconvulsive Therapy to Improve Anorexia Nervosa in the Absence of Other Psychiatric Comorbidities: A Case Report. J. ECT 2020, 36, e44–e45. [Google Scholar] [CrossRef] [PubMed]
  16. Zipfel, S.; Giel, K.E.; Bulik, C.M.; Hay, P.; Schmidt, U. Anorexia Nervosa: Aetiology, Assessment, and Treatment. Lancet Psychiatry 2015, 2, 1099–1111. [Google Scholar] [CrossRef] [PubMed]
  17. Watson, H.J.; Yilmaz, Z.; Thornton, L.M.; Hübel, C.; Coleman, J.R.I.; Gaspar, H.A.; Bryois, J.; Hinney, A.; Leppä, V.M.; Mattheisen, M.; et al. Genome-Wide Association Study Identifies Eight Risk Loci and Implicates Metabo-Psychiatric Origins for Anorexia Nervosa. Nat. Genet. 2019, 51, 1207–1214. [Google Scholar] [CrossRef] [PubMed]
  18. Lilenfeld, L.R.; Kaye, W.H.; Greeno, C.G.; Merikangas, K.R.; Plotnicov, K.; Pollice, C.; Rao, R.; Strober, M.; Bulik, C.M.; Nagy, L. A Controlled Family Study of Anorexia Nervosa and Bulimia Nervosa: Psychiatric Disorders in First-Degree Relatives and Effects of Proband Comorbidity. Arch. Gen. Psychiatry 1998, 55, 603. [Google Scholar] [CrossRef]
  19. Strober, M.; Freeman, R.; Lampert, C.; Diamond, J.; Kaye, W. Controlled Family Study of Anorexia Nervosa and Bulimia Nervosa: Evidence of Shared Liability and Transmission of Partial Syndromes. Am. J. Psychiatry 2000, 157, 393–401. [Google Scholar] [CrossRef] [PubMed]
  20. Bulik, C.; Yilmaz, Z.; HArdaway, A. Genetics and Epigenetics of Eating Disorders. Adv. Genomics Genet. 2015, 2015, 131. [Google Scholar] [CrossRef]
  21. Versini, A.; Ramoz, N.; Le Strat, Y.; Scherag, S.; Ehrlich, S.; Boni, C.; Hinney, A.; Hebebrand, J.; Romo, L.; Guelfi, J.-D.; et al. Estrogen Receptor 1 Gene (ESR1) Is Associated with Restrictive Anorexia Nervosa. Neuropsychopharmacology 2010, 35, 1818–1825. [Google Scholar] [CrossRef]
  22. Baker, J.H.; Schaumberg, K.; Munn-Chernoff, M.A. Genetics of Anorexia Nervosa. Curr. Psychiatry Rep. 2017, 19, 84. [Google Scholar] [CrossRef] [PubMed]
  23. Abou Al Hassan, S.; Cutinha, D.; Mattar, L. The Impact of COMT, BDNF and 5-HTT Brain-Genes on the Development of Anorexia Nervosa: A Systematic Review. Eat. Weight Disord. EWD 2021, 26, 1323–1344. [Google Scholar] [CrossRef] [PubMed]
  24. Rybakowski, F.; Dmitrzak-Weglarz, M.; Szczepankiewicz, A.; Skibinska, M.; Slopien, A.; Rajewski, A.; Hauser, J. Brain Derived Neurotrophic Factor Gene Val66Met and -270C/T Polymorphisms and Personality Traits Predisposing to Anorexia Nervosa. Neuro Endocrinol. Lett. 2007, 28, 153–158. [Google Scholar] [PubMed]
  25. Clarke, J.; Ramoz, N.; Fladung, A.-K.; Gorwood, P. Higher Reward Value of Starvation Imagery in Anorexia Nervosa and Association with the Val66Met BDNF Polymorphism. Transl. Psychiatry 2016, 6, e829. [Google Scholar] [CrossRef]
  26. Aid, T.; Kazantseva, A.; Piirsoo, M.; Palm, K.; Timmusk, T. Mouse and Rat BDNF Gene Structure and Expression Revisited. J. Neurosci. Res. 2007, 85, 525–535. [Google Scholar] [CrossRef] [PubMed]
  27. Barde, Y.A.; Edgar, D.; Thoenen, H. Purification of a New Neurotrophic Factor from Mammalian Brain. EMBO J. 1982, 1, 549–553. [Google Scholar] [CrossRef] [PubMed]
  28. Klein, R.; Parada, L.F.; Coulier, F.; Barbacid, M. TrkB, a Novel Tyrosine Protein Kinase Receptor Expressed during Mouse Neural Development. EMBO J. 1989, 8, 3701–3709. [Google Scholar] [CrossRef] [PubMed]
  29. Klein, R.; Nanduri, V.; Jing, S.; Lamballe, F.; Tapley, P.; Bryant, S.; Cordon-Cardo, C.; Jones, K.R.; Reichardt, L.F.; Barbacid, M. The TrkB Tyrosine Protein Kinase Is a Receptor for Brain-Derived Neurotrophic Factor and Neurotrophin-3. Cell 1991, 66, 395–403. [Google Scholar] [CrossRef] [PubMed]
  30. Keifer, J.; Sabirzhanov, B.E.; Zheng, Z.; Li, W.; Clark, T.G. Cleavage of ProBDNF to BDNF by a Tolloid-Like Metalloproteinase Is Required for Acquisition of In Vitro Eyeblink Classical Conditioning. J. Neurosci. 2009, 29, 14956–14964. [Google Scholar] [CrossRef]
  31. Barde, Y.-A. The Nerve Growth Factor Family. Prog. Growth Factor Res. 1990, 2, 237–248. [Google Scholar] [CrossRef]
  32. Alderson, R.F.; Alterman, A.L.; Barde, Y.-A.; Lindsay, R.M. Brain-Derived Neurotrophic Factor Increases Survival and Differentiated Functions of Rat Septal Cholinergic Neurons in Culture. Neuron 1990, 5, 297–306. [Google Scholar] [CrossRef] [PubMed]
  33. Lindholm, D.; Dechant, G.; Heisenberg, C.-P.; Thoenen, H. Brain-Derived Neurotrophic Factor Is a Survival Factor for Cultured Rat Cerebellar Granule Neurons and Protects Them Against Glutamate-Induced Neurotoxicity. Eur. J. Neurosci. 1993, 5, 1455–1464. [Google Scholar] [CrossRef] [PubMed]
  34. Ji, Y.; Pang, P.T.; Feng, L.; Lu, B. Cyclic AMP Controls BDNF-Induced TrkB Phosphorylation and Dendritic Spine Formation in Mature Hippocampal Neurons. Nat. Neurosci. 2005, 8, 164–172. [Google Scholar] [CrossRef] [PubMed]
  35. Lu, Y.; Christian, K.; Lu, B. BDNF: A Key Regulator for Protein-Synthesis Dependent LTP and Long-Term Memory? Neurobiol. Learn. Mem. 2008, 89, 312–323. [Google Scholar] [CrossRef] [PubMed]
  36. Teng, H.K.; Teng, K.K.; Lee, R.; Wright, S.; Tevar, S.; Almeida, R.D.; Kermani, P.; Torkin, R.; Chen, Z.-Y.; Lee, F.S.; et al. ProBDNF Induces Neuronal Apoptosis via Activation of a Receptor Complex of P75NTR and Sortilin. J. Neurosci. 2005, 25, 5455–5463. [Google Scholar] [CrossRef] [PubMed]
  37. Singh, K.K.; Park, K.J.; Hong, E.J.; Kramer, B.M.; Greenberg, M.E.; Kaplan, D.R.; Miller, F.D. Developmental Axon Pruning Mediated by BDNF-P75NTR–Dependent Axon Degeneration. Nat. Neurosci. 2008, 11, 649–658. [Google Scholar] [CrossRef] [PubMed]
  38. Orefice, L.L.; Shih, C.-C.; Xu, H.; Waterhouse, E.G.; Xu, B. Control of Spine Maturation and Pruning through ProBDNF Synthesized and Released in Dendrites. Mol. Cell. Neurosci. 2016, 71, 66–79. [Google Scholar] [CrossRef] [PubMed]
  39. Ernfors, P.; Lee, K.F.; Jaenisch, R. Mice Lacking Brain-Derived Neurotrophic Factor Develop with Sensory Deficits. Nature 1994, 368, 147–150. [Google Scholar] [CrossRef] [PubMed]
  40. Neves-Pereira, M.; Mundo, E.; Muglia, P.; King, N.; Macciardi, F.; Kennedy, J.L. The Brain-Derived Neurotrophic Factor Gene Confers Susceptibility to Bipolar Disorder: Evidence from a Family-Based Association Study. Am. J. Hum. Genet. 2002, 71, 651–655. [Google Scholar] [CrossRef]
  41. Egan, M.F.; Kojima, M.; Callicott, J.H.; Goldberg, T.E.; Kolachana, B.S.; Bertolino, A.; Zaitsev, E.; Gold, B.; Goldman, D.; Dean, M.; et al. The BDNF Val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function. Cell 2003, 112, 257–269. [Google Scholar] [CrossRef]
  42. Chen, Z.-Y.; Patel, P.D.; Sant, G.; Meng, C.-X.; Teng, K.K.; Hempstead, B.L.; Lee, F.S. Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons. J. Neurosci. Off. J. Soc. Neurosci. 2004, 24, 4401–4411. [Google Scholar] [CrossRef] [PubMed]
  43. Chiaruttini, C.; Vicario, A.; Li, Z.; Baj, G.; Braiuca, P.; Wu, Y.; Lee, F.S.; Gardossi, L.; Baraban, J.M.; Tongiorgi, E. Dendritic Trafficking of BDNF MRNA Is Mediated by Translin and Blocked by the G196A (Val66Met) Mutation. Proc. Natl. Acad. Sci. USA 2009, 106, 16481–16486. [Google Scholar] [CrossRef] [PubMed]
  44. Ursini, G.; Cavalleri, T.; Fazio, L.; Angrisano, T.; Iacovelli, L.; Porcelli, A.; Maddalena, G.; Punzi, G.; Mancini, M.; Gelao, B.; et al. BDNF Rs6265 Methylation and Genotype Interact on Risk for Schizophrenia. Epigenetics 2016, 11, 11–23. [Google Scholar] [CrossRef] [PubMed]
  45. Tongiorgi, E.; Righi, M.; Cattaneo, A. Activity-Dependent Dendritic Targeting of BDNF and TrkB MRNAs in Hippocampal Neurons. J. Neurosci. 1997, 17, 9492–9505. [Google Scholar] [CrossRef] [PubMed]
  46. McHughen, S.A.; Rodriguez, P.F.; Kleim, J.A.; Kleim, E.D.; Crespo, L.M.; Procaccio, V.; Cramer, S.C. BDNF Val66Met Polymorphism Influences Motor System Function in the Human Brain. Cereb. Cortex 2010, 20, 1254–1262. [Google Scholar] [CrossRef] [PubMed]
  47. Edelmann, E.; Leßmann, V.; Brigadski, T. Pre- and Postsynaptic Twists in BDNF Secretion and Action in Synaptic Plasticity. Neuropharmacology 2014, 76, 610–627. [Google Scholar] [CrossRef]
  48. Ieraci, A.; Mallei, A.; Popoli, M. Social Isolation Stress Induces Anxious-Depressive-Like Behavior and Alterations of Neuroplasticity-Related Genes in Adult Male Mice. Neural Plast. 2016, 2016, 6212983. [Google Scholar] [CrossRef] [PubMed]
  49. Uegaki, K.; Kumanogoh, H.; Mizui, T.; Hirokawa, T.; Ishikawa, Y.; Kojima, M. BDNF Binds Its Pro-Peptide with High Affinity and the Common Val66Met Polymorphism Attenuates the Interaction. Int. J. Mol. Sci. 2017, 18, 1042. [Google Scholar] [CrossRef]
  50. Brandys, M.K.; Kas, M.J.H.; van Elburg, A.A.; Ophoff, R.; Slof-Op’t Landt, M.C.T.; Middeldorp, C.M.; Boomsma, D.I.; van Furth, E.F.; Slagboom, P.E.; Adan, R.A.H. The Val66Met Polymorphism of the BDNF Gene in Anorexia Nervosa: New Data and a Meta-Analysis. World J. Biol. Psychiatry Off. J. World Fed. Soc. Biol. Psychiatry 2013, 14, 441–451. [Google Scholar] [CrossRef]
  51. Lisoway, A.; Sonley, A.; Law, J.; Zai, C.; Chapman, A.; McMain, S.; Kennedy, J. Brain-Derived Neurotrophic Factor (BDNF Val66Met) in Borderline Personality Disorder: Associated with Eating Disorder Comorbidity but Not Psychotherapy Response. Pers. Med. Psychiatry 2024, 43–44, 100114. [Google Scholar] [CrossRef]
  52. Ribases, M.; Gratacos, M.; Fernandez-Aranda, F.; Bellodi, L.; Boni, C.; Anderluh, M.; Cavallini, M.C.; Cellini, E.; Bella, D.D.; Erzegovesi, S.; et al. Association of BDNF with Restricting Anorexia Nervosa and Minimum Body Mass Index: A Family-Based Association Study of Eight European Populations. Eur. J. Hum. Genet. 2005, 13, 428–434. [Google Scholar] [CrossRef] [PubMed]
  53. Koizumi, H.; Hashimoto, K.; Itoh, K.; Nakazato, M.; Shimizu, E.; Ohgake, S.; Koike, K.; Okamura, N.; Matsushita, S.; Suzuki, K.; et al. Association between the Brain-derived Neurotrophic Factor 196G/A Polymorphism and Eating Disorders. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2004, 127B, 125–127. [Google Scholar] [CrossRef]
  54. Mercader, J.M.; Ribasés, M.; Gratacòs, M.; González, J.R.; Bayés, M.; de Cid, R.; Badía, A.; Fernández-Aranda, F.; Estivill, X. Altered Brain-Derived Neurotrophic Factor Blood Levels and Gene Variability Are Associated with Anorexia and Bulimia. Genes Brain Behav. 2007, 6, 706–716. [Google Scholar] [CrossRef]
  55. Tyszkiewicz-Nwafor, M.; Rybakowski, F.; Dmitrzak-Weglarz, M.; Skibinska, M.; Paszynska, E.; Dutkiewicz, A.; Słopien, A. Brain-Derived Neurotrophic Factor and Oxytocin Signaling in Association With Clinical Symptoms in Adolescent Inpatients With Anorexia Nervosa—A Longitudinal Study. Front. Psychiatry 2020, 10, 1032. [Google Scholar] [CrossRef] [PubMed]
  56. Borsdorf, B.; Dahmen, B.; Buehren, K.; Dempfle, A.; Egberts, K.; Ehrlich, S.; Fleischhaker, C.; Konrad, K.; Schwarte, R.; Timmesfeld, N.; et al. BDNF Levels in Adolescent Patients with Anorexia Nervosa Increase Continuously to Supranormal Levels 2.5 Years after First Hospitalization. J. Psychiatry Neurosci. 2021, 46, E568–E578. [Google Scholar] [CrossRef]
  57. Xu, H.; Wang, J.; Zhang, K.; Zhao, M.; Ellenbroek, B.; Shao, F.; Wang, W. Effects of Adolescent Social Stress and Antidepressant Treatment on Cognitive Inflexibility and Bdnf Epigenetic Modifications in the MPFC of Adult Mice. Psychoneuroendocrinology 2018, 88, 92–101. [Google Scholar] [CrossRef]
  58. Houlton, J.; Zhou, L.Y.Y.; Barwick, D.; Gowing, E.K.; Clarkson, A.N. Stroke Induces a BDNF-Dependent Improvement in Cognitive Flexibility in Aged Mice. Neural Plast. 2019, 2019, 1460890. [Google Scholar] [CrossRef] [PubMed]
  59. Mora, E.; Portella, M.J.; Piñol-Ripoll, G.; López, R.; Cuadras, D.; Forcada, I.; Teres, M.; Vieta, E.; Mur, M. High BDNF Serum Levels Are Associated to Good Cognitive Functioning in Bipolar Disorder. Eur. Psychiatry 2019, 60, 97–107. [Google Scholar] [CrossRef] [PubMed]
  60. Nakazato, M.; Tchanturia, K.; Schmidt, U.; Campbell, I.C.; Treasure, J.; Collier, D.A.; Hashimoto, K.; Iyo, M. Brain-Derived Neurotrophic Factor (BDNF) and Set-Shifting in Currently Ill and Recovered Anorexia Nervosa (AN) Patients. Psychol. Med. 2009, 39, 1029–1035. [Google Scholar] [CrossRef]
  61. Gamero-Villarroel, C.; Gordillo, I.; Carrillo, J.A.; García-Herráiz, A.; Flores, I.; Jiménez, M.; Monge, M.; Rodríguez-López, R.; Gervasini, G. BDNF Genetic Variability Modulates Psychopathological Symptoms in Patients with Eating Disorders. Eur. Child Adolesc. Psychiatry 2014, 23, 669–679. [Google Scholar] [CrossRef]
  62. Chowdhury, T.G.; Chen, Y.-W.; Aoki, C. Using the Activity-Based Anorexia Rodent Model to Study the Neurobiological Basis of Anorexia Nervosa. J. Vis. Exp. 2015, 22, 52927. [Google Scholar] [CrossRef]
  63. Duriez, P.; Nilsson, I.A.K.; Le Thuc, O.; Alexandre, D.; Chartrel, N.; Rovere, C.; Chauveau, C.; Gorwood, P.; Tolle, V.; Viltart, O. Exploring the Mechanisms of Recovery in Anorexia Nervosa through a Translational Approach: From Original Ecological Measurements in Human to Brain Tissue Analyses in Mice. Nutrients 2021, 13, 2786. [Google Scholar] [CrossRef] [PubMed]
  64. Gelegen, C.; Van Den Heuvel, J.; Collier, D.A.; Campbell, I.C.; Oppelaar, H.; Hessel, E.; Kas, M.J.H. Dopaminergic and Brain-derived Neurotrophic Factor Signalling in Inbred Mice Exposed to a Restricted Feeding Schedule. Genes Brain Behav. 2008, 7, 552–559. [Google Scholar] [CrossRef] [PubMed]
  65. Ho, E.V.; Klenotich, S.J.; McMurray, M.S.; Dulawa, S.C. Activity-Based Anorexia Alters the Expression of BDNF Transcripts in the Mesocorticolimbic Reward Circuit. PLoS ONE 2016, 11, e0166756. [Google Scholar] [CrossRef] [PubMed]
  66. Mottarlini, F.; Rizzi, B.; Targa, G.; Fumagalli, F.; Caffino, L. Long-Lasting BDNF Signaling Alterations in the Amygdala of Adolescent Female Rats Exposed to the Activity-Based Anorexia Model. Front. Behav. Neurosci. 2022, 16, 1087075. [Google Scholar] [CrossRef] [PubMed]
  67. Kennerley, S.W.; Walton, M.E. Decision Making and Reward in Frontal Cortex: Complementary Evidence from Neurophysiological and Neuropsychological Studies. Behav. Neurosci. 2011, 125, 297–317. [Google Scholar] [CrossRef] [PubMed]
  68. Frank, G.K.W. Altered Brain Reward Circuits in Eating Disorders: Chicken or Egg? Curr. Psychiatry Rep. 2013, 15, 396. [Google Scholar] [CrossRef] [PubMed]
  69. Ruscitti, C.; Rufino, K.; Goodwin, N.; Wagner, R. Difficulties in Emotion Regulation in Patients with Eating Disorders. Borderline Personal. Disord. Emot. Dysregulation 2016, 3, 3. [Google Scholar] [CrossRef] [PubMed]
  70. Trutti, A.C.; Mulder, M.J.; Hommel, B.; Forstmann, B.U. Functional Neuroanatomical Review of the Ventral Tegmental Area. NeuroImage 2019, 191, 258–268. [Google Scholar] [CrossRef]
  71. Zhu, Y.; Gao, H.; Tong, L.; Li, Z.; Wang, L.; Zhang, C.; Yang, Q.; Yan, B. Emotion Regulation of Hippocampus Using Real-Time FMRI Neurofeedback in Healthy Human. Front. Hum. Neurosci. 2019, 13, 242. [Google Scholar] [CrossRef]
  72. Di Lodovico, L.; Versini, A.; Lachatre, M.; Marcheselli, J.; Ramoz, N.; Gorwood, P. Is Decision-Making Impairment an Endophenotype of Anorexia Nervosa? Eur. Psychiatry 2022, 65, e68. [Google Scholar] [CrossRef]
  73. Del Arco, A.; Segovia, G.; de Blas, M.; Garrido, P.; Acuña-Castroviejo, D.; Pamplona, R.; Mora, F. Prefrontal Cortex, Caloric Restriction and Stress during Aging: Studies on Dopamine and Acetylcholine Release, BDNF and Working Memory. Behav. Brain Res. 2011, 216, 136–145. [Google Scholar] [CrossRef] [PubMed]
  74. Pan, Y.; Chau, L.; Liu, S.; Avshalumov, M.V.; Rice, M.E.; Carr, K.D. A Food Restriction Protocol That Increases Drug Reward Decreases Tropomyosin Receptor Kinase B in the Ventral Tegmental Area, with No Effect on Brain-Derived Neurotrophic Factor or Tropomyosin Receptor Kinase B Protein Levels in Dopaminergic Forebrain Regions. Neuroscience 2011, 197, 330–338. [Google Scholar] [CrossRef]
  75. Baranowski, B.J.; Hayward, G.C.; Marko, D.M.; MacPherson, R.E.K. Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling. Front. Cell. Neurosci. 2021, 15, 665867. [Google Scholar] [CrossRef]
  76. Kanoski, S.; Meisel, R.; Mullins, A.; Davidson, T. The Effects of Energy-Rich Diets on Discrimination Reversal Learning and on BDNF in the Hippocampus and Prefrontal Cortex of the Rat. Behav. Brain Res. 2007, 182, 57–66. [Google Scholar] [CrossRef]
  77. Murakami, S.; Imbe, H.; Morikawa, Y.; Kubo, C.; Senba, E. Chronic Stress, as Well as Acute Stress, Reduces BDNF MRNA Expression in the Rat Hippocampus but Less Robustly. Neurosci. Res. 2005, 53, 129–139. [Google Scholar] [CrossRef]
  78. Kaptan, Z.; Akgün-Dar, K.; Kapucu, A.; Dedeakayoğulları, H.; Batu, Ş.; Üzüm, G. Long Term Consequences on Spatial Learning-Memory of Low-Calorie Diet during Adolescence in Female Rats; Hippocampal and Prefrontal Cortex BDNF Level, Expression of NeuN and Cell Proliferation in Dentate Gyrus. Brain Res. 2015, 1618, 194–204. [Google Scholar] [CrossRef] [PubMed]
  79. Duan, W.; Lee, J.; Guo, Z.; Mattson, M.P. Dietary Restriction Stimulates BDNF Production in the Brain and Thereby Protects Neurons Against Excitotoxic Injury. J. Mol. Neurosci. 2001, 16, 1–12. [Google Scholar] [CrossRef] [PubMed]
  80. Serra, M.; Poddighe, L.; Boi, M.; Sanna, F.; Piludu, M.; Sanna, F.; Corda, M.; Giorgi, O.; Quartu, M. Effect of Acute Stress on the Expression of BDNF, TrkB, and PSA-NCAM in the Hippocampus of the Roman Rats: A Genetic Model of Vulnerability/Resistance to Stress-Induced Depression. Int. J. Mol. Sci. 2018, 19, 3745. [Google Scholar] [CrossRef]
  81. Gilland, K.E.; Fox, E.A. Effect of Food Deprivation or Short-Term Western Diet Feeding on BDNF Protein Expression in the Hypothalamic Arcuate, Paraventricular, and Ventromedial Nuclei. Am. J. Physiol.-Regul. Integr. Comp. Physiol. 2017, 312, R611–R625. [Google Scholar] [CrossRef]
  82. Andrade, J.P.; Mesquita, R.; Assunção, M.; Pereira, P.A. Effects of Food Restriction on Synthesis and Expression of Brain-Derived Neurotrophic Factor and Tyrosine Kinase B in Dentate Gyrus Granule Cells of Adult Rats. Neurosci. Lett. 2006, 399, 135–140. [Google Scholar] [CrossRef]
  83. Baik, S.; Rajeev, V.; Fann, D.Y.; Jo, D.; Arumugam, T.V. Intermittent Fasting Increases Adult Hippocampal Neurogenesis. Brain Behav. 2020, 10, e01444. [Google Scholar] [CrossRef]
  84. Yu, Y.; Wang, Q.; Huang, X.-F. Energy-Restricted Pair-Feeding Normalizes Low Levels of Brain-Derived Neurotrophic Factor/Tyrosine Kinase B MRNA Expression in the Hippocampus, but Not Ventromedial Hypothalamic Nucleus, in Diet-Induced Obese Mice. Neuroscience 2009, 160, 295–306. [Google Scholar] [CrossRef]
  85. Liu, X.; Zhu, Z.; Kalyani, M.; Janik, J.M.; Shi, H. Effects of Energy Status and Diet on Bdnf Expression in the Ventromedial Hypothalamus of Male and Female Rats. Physiol. Behav. 2014, 130, 99–107. [Google Scholar] [CrossRef]
  86. Rage, F.; Givalois, L.; Marmigère, F.; Tapia-Arancibia, L.; Arancibia, S. Immobilization Stress Rapidly Modulates BDNF MRNA Expression in the Hypothalamus of Adult Male Rats. Neuroscience 2002, 112, 309–318. [Google Scholar] [CrossRef]
  87. Schaich, C.L.; Wellman, T.L.; Einwag, Z.; Dutko, R.A.; Erdos, B. Inhibition of BDNF Signaling in the Paraventricular Nucleus of the Hypothalamus Lowers Acute Stress-Induced Pressor Responses. J. Neurophysiol. 2018, 120, 633–643. [Google Scholar] [CrossRef]
  88. Bastioli, G.; Arnold, J.C.; Mancini, M.; Mar, A.C.; Gamallo-Lana, B.; Saadipour, K.; Chao, M.V.; Rice, M.E. Voluntary Exercise Boosts Striatal Dopamine Release: Evidence for the Necessary and Sufficient Role of BDNF. J. Neurosci. 2022, 42, 4725–4736. [Google Scholar] [CrossRef]
  89. Miyanishi, H.; Muramatsu, S.-I.; Nitta, A. Striatal Shati/Nat8l-BDNF Pathways Determine the Sensitivity to Social Defeat Stress in Mice through Epigenetic Regulation. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2021, 46, 1594–1605. [Google Scholar] [CrossRef]
  90. Krishnan, V.; Han, M.-H.; Graham, D.L.; Berton, O.; Renthal, W.; Russo, S.J.; LaPlant, Q.; Graham, A.; Lutter, M.; Lagace, D.C.; et al. Molecular Adaptations Underlying Susceptibility and Resistance to Social Defeat in Brain Reward Regions. Cell 2007, 131, 391–404. [Google Scholar] [CrossRef]
  91. Serra, M.P.; Sanna, F.; Boi, M.; Poddighe, L.; Secci, L.; Trucas, M.; Fernández-Teruel, A.; Corda, M.G.; Giorgi, O.; Quartu, M. Acute Stress Induces Different Changes on the Expression of BDNF and TrkB in the Mesocorticolimbic System of Two Lines of Rats Differing in Their Response to Stressors. Int. J. Mol. Sci. 2022, 23, 14995. [Google Scholar] [CrossRef]
  92. Zhao, M.; Zhu, Z.; Li, H.; Wang, W.; Cheng, S.; Qin, X.; Wu, H.; Liu, D.; Pan, F. Effects of Traumatic Stress in Adolescence on PTSD-like Behaviors, Dendrite Development, and H3K9me2/BDNF Expression in the Amygdala of Male Rats. J. Affect. Disord. 2022, 296, 388–399. [Google Scholar] [CrossRef]
  93. Miyamoto, T.; Hashimoto, S.; Yanamoto, H.; Ikawa, M.; Nakano, Y.; Sekiyama, T.; Kou, K.; Kashiwamura, S.; Takeda, C.; Fujioka, H. Response of Brain-derived Neurotrophic Factor to Combining Cognitive and Physical Exercise. Eur. J. Sport Sci. 2018, 18, 1119–1127. [Google Scholar] [CrossRef]
  94. Zhou, L.; Xiong, J.; Lim, Y.; Ruan, Y.; Huang, C.; Zhu, Y.; Zhong, J.; Xiao, Z.; Zhou, X.-F. Upregulation of Blood ProBDNF and Its Receptors in Major Depression. J. Affect. Disord. 2013, 150, 776–784. [Google Scholar] [CrossRef]
  95. Herhaus, B.; Heni, M.; Bloch, W.; Petrowski, K. Acute and Chronic Psychosocial Stress by the Brain-Derived Neurotrophic Factor in Male Humans: A Highly Standardized and Controlled Study. medRxiv 2023. [Google Scholar] [CrossRef]
  96. Beeler, J.; Burghardt, N. Activity-Based Anorexia for Modeling Vulnerability and Resilience in Mice. Bio-Protocol 2021, 11, e4009. [Google Scholar] [CrossRef]
  97. Pietrucci, C.L.; Milton, L.K.; Greaves, E.; Stefanidis, A.; van den Buuse, M.; Oldfield, B.J.; Foldi, C.J. The BDNF Val66Met Polymorphism Does Not Increase Susceptibility to Activity-Based Anorexia in Rats. Biology 2022, 11, 623. [Google Scholar] [CrossRef]
  98. Chen, Y.-W.; Surgent, O.; Rana, B.S.; Lee, F.; Aoki, C. Variant BDNF-Val66Met Polymorphism Is Associated with Layer-Specific Alterations in GABAergic Innervation of Pyramidal Neurons, Elevated Anxiety and Reduced Vulnerability of Adolescent Male Mice to Activity-Based Anorexia. Cereb. Cortex 2017, 27, 3980–3993. [Google Scholar] [CrossRef]
  99. Madra, M.; Zeltser, L.M. BDNF-Val66Met Variant and Adolescent Stress Interact to Promote Susceptibility to Anorexic Behavior in Mice. Transl. Psychiatry 2016, 6, e776. [Google Scholar] [CrossRef]
  100. Donohoe, T.P. Stress-Induced Anorexia: Implications for Anorexia Nervosa. Life Sci. 1984, 34, 203–218. [Google Scholar] [CrossRef]
  101. Guarda, A.S.; Schreyer, C.C.; Boersma, G.J.; Tamashiro, K.L.; Moran, T.H. Anorexia Nervosa as a Motivated Behavior: Relevance of Anxiety, Stress, Fear and Learning. Physiol. Behav. 2015, 152, 466–472. [Google Scholar] [CrossRef]
  102. Kozlovsky, N.; Matar, M.A.; Kaplan, Z.; Kotler, M.; Zohar, J.; Cohen, H. Long-Term down-Regulation of BDNF MRNA in Rat Hippocampal CA1 Subregion Correlates with PTSD-like Behavioural Stress Response. Int. J. Neuropsychopharmacol. 2007, 10, 741–758. [Google Scholar] [CrossRef]
  103. Hou, L.; Qi, Y.; Sun, H.; Wang, G.; Li, Q.; Wang, Y.; Zhang, Z.; Du, Z.; Sun, L. Applying Ketamine to Alleviate the PTSD-like Effects by Regulating the HCN1-Related BDNF. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018, 86, 313–321. [Google Scholar] [CrossRef]
  104. Fang, W.; Zhang, J.; Hong, L.; Huang, W.; Dai, X.; Ye, Q.; Chen, X. Metformin Ameliorates Stress-Induced Depression-like Behaviors via Enhancing the Expression of BDNF by Activating AMPK/CREB-Mediated Histone Acetylation. J. Affect. Disord. 2020, 260, 302–313. [Google Scholar] [CrossRef]
  105. Eisch, A.J.; Bolaños, C.A.; de Wit, J.; Simonak, R.D.; Pudiak, C.M.; Barrot, M.; Verhaagen, J.; Nestler, E.J. Brain-Derived Neurotrophic Factor in the Ventral Midbrain-Nucleus Accumbens Pathway: A Role in Depression. Biol. Psychiatry 2003, 54, 994–1005. [Google Scholar] [CrossRef]
  106. Berton, O.; McClung, C.A.; Dileone, R.J.; Krishnan, V.; Renthal, W.; Russo, S.J.; Graham, D.; Tsankova, N.M.; Bolanos, C.A.; Rios, M.; et al. Essential Role of BDNF in the Mesolimbic Dopamine Pathway in Social Defeat Stress. Science 2006, 311, 864–868. [Google Scholar] [CrossRef]
  107. Darvas, M.; Palmiter, R.D. Contributions of Striatal Dopamine Signaling to the Modulation of Cognitive Flexibility. Biol. Psychiatry 2011, 69, 704–707. [Google Scholar] [CrossRef]
  108. Miyanishi, H.; Nitta, A. A Role of BDNF in the Depression Pathogenesis and a Potential Target as Antidepressant: The Modulator of Stress Sensitivity “Shati/Nat8l-BDNF System” in the Dorsal Striatum. Pharmaceuticals 2021, 14, 889. [Google Scholar] [CrossRef]
  109. Taliaz, D.; Nagaraj, V.; Haramati, S.; Chen, A.; Zangen, A. Altered Brain-Derived Neurotrophic Factor Expression in the Ventral Tegmental Area, but Not in the Hippocampus, Is Essential for Antidepressant-Like Effects of Electroconvulsive Therapy. Biol. Psychiatry 2013, 74, 305–312. [Google Scholar] [CrossRef]
  110. Banerjee, R.; Ghosh, A.K.; Ghosh, B.; Bhattacharyya, S.; Mondal, A.C. Decreased MRNA and Protein Expression of BDNF, NGF, and Their Receptors in the Hippocampus from Suicide: An Analysis in Human Postmortem Brain. Clin. Med. Insights Pathol. 2013, 6, 1–11. [Google Scholar] [CrossRef]
  111. Yu, H.; Wang, D.-D.; Wang, Y.; Liu, T.; Lee, F.S.; Chen, Z.-Y. Variant Brain-Derived Neurotrophic Factor Val66Met Polymorphism Alters Vulnerability to Stress and Response to Antidepressants. J. Neurosci. 2012, 32, 4092–4101. [Google Scholar] [CrossRef]
  112. Hosang, G.M.; Shiles, C.; Tansey, K.E.; McGuffin, P.; Uher, R. Interaction between Stress and the BDNFVal66Met Polymorphism in Depression: A Systematic Review and Meta-Analysis. BMC Med. 2014, 12, 7. [Google Scholar] [CrossRef]
  113. de Castro-Catala, M.; van Nierop, M.; Barrantes-Vidal, N.; Cristóbal-Narváez, P.; Sheinbaum, T.; Kwapil, T.R.; Peña, E.; Jacobs, N.; Derom, C.; Thiery, E.; et al. Childhood Trauma, BDNF Val66Met and Subclinical Psychotic Experiences. Attempt at Replication in Two Independent Samples. J. Psychiatr. Res. 2016, 83, 121–129. [Google Scholar] [CrossRef]
  114. Lehto, K.; Mäestu, J.; Kiive, E.; Veidebaum, T.; Harro, J. BDNF Val66Met Genotype and Neuroticism Predict Life Stress: A Longitudinal Study from Childhood to Adulthood. Eur. Neuropsychopharmacol. J. Eur. Coll. Neuropsychopharmacol. 2016, 26, 562–569. [Google Scholar] [CrossRef]
  115. González-Castro, T.B.; Salas-Magaña, M.; Juárez-Rojop, I.E.; López-Narváez, M.L.; Tovilla-Zárate, C.A.; Hernández-Díaz, Y. Exploring the Association between BDNF Val66Met Polymorphism and Suicidal Behavior: Meta-Analysis and Systematic Review. J. Psychiatr. Res. 2017, 94, 208–217. [Google Scholar] [CrossRef]
  116. Gatt, J.M.; Nemeroff, C.B.; Dobson-Stone, C.; Paul, R.H.; Bryant, R.A.; Schofield, P.R.; Gordon, E.; Kemp, A.H.; Williams, L.M. Interactions between BDNF Val66Met Polymorphism and Early Life Stress Predict Brain and Arousal Pathways to Syndromal Depression and Anxiety. Mol. Psychiatry 2009, 14, 681–695. [Google Scholar] [CrossRef]
  117. Chen, J.; Li, X.; McGue, M. Interacting Effect of BDNF VAL66MET Polymorphism and Stressful Life Events on Adolescent Depression. Genes Brain Behav. 2012, 11, 958–965. [Google Scholar] [CrossRef]
  118. Chen, C.; Ji, M.; Xu, Q.; Zhang, Y.; Sun, Q.; Liu, J.; Zhu, S.; Li, W. Sevoflurane Attenuates Stress-Enhanced Fear Learning by Regulating Hippocampal BDNF Expression and Akt/GSK-3β Signaling Pathway in a Rat Model of Post-Traumatic Stress Disorder. J. Anesth. 2015, 29, 600–608. [Google Scholar] [CrossRef]
  119. Shalev, I.; Lerer, E.; Israel, S.; Uzefovsky, F.; Gritsenko, I.; Mankuta, D.; Ebstein, R.P.; Kaitz, M. BDNF Val66Met Polymorphism Is Associated with HPA Axis Reactivity to Psychological Stress Characterized by Genotype and Gender Interactions. Psychoneuroendocrinology 2009, 34, 382–388. [Google Scholar] [CrossRef]
  120. Alexander, N.; Osinsky, R.; Schmitz, A.; Mueller, E.; Kuepper, Y.; Hennig, J. The BDNF Val66Met Polymorphism Affects HPA-Axis Reactivity to Acute Stress. Psychoneuroendocrinology 2010, 35, 949–953. [Google Scholar] [CrossRef]
  121. Mayo-Martínez, L.; Rupérez, F.J.; Martos-Moreno, G.Á.; Graell, M.; Barbas, C.; Argente, J.; García, A. Unveiling Metabolic Phenotype Alterations in Anorexia Nervosa through Metabolomics. Nutrients 2021, 13, 4249. [Google Scholar] [CrossRef]
  122. Hill, J. PVN Pathways Controlling Energy Homeostasis. Indian J. Endocrinol. Metab. 2012, 16, 627. [Google Scholar] [CrossRef]
  123. An, J.J.; Liao, G.-Y.; Kinney, C.E.; Sahibzada, N.; Xu, B. Discrete BDNF Neurons in the Paraventricular Hypothalamus Control Feeding and Energy Expenditure. Cell Metab. 2015, 22, 175–188. [Google Scholar] [CrossRef]
  124. Pelleymounter, M.A.; Cullen, M.J.; Wellman, C.L. Characteristics of BDNF-Induced Weight Loss. Exp. Neurol. 1995, 131, 229–238. [Google Scholar] [CrossRef]
  125. Wang, P.; Loh, K.H.; Wu, M.; Morgan, D.A.; Schneeberger, M.; Yu, X.; Chi, J.; Kosse, C.; Kim, D.; Rahmouni, K.; et al. A Leptin-BDNF Pathway Regulating Sympathetic Innervation of Adipose Tissue. Nature 2020, 583, 839–844. [Google Scholar] [CrossRef]
  126. Wu, S.-W.; Xu, B. Rapid and Lasting Effects of Activating BDNF-Expressing PVH Neurons on Energy Balance. eNeuro 2022, 9, ENEURO.0009-22.2022. [Google Scholar] [CrossRef]
  127. Liao, G.-Y.; Bouyer, K.; Kamitakahara, A.; Sahibzada, N.; Wang, C.-H.; Rutlin, M.; Simerly, R.B.; Xu, B. Brain-Derived Neurotrophic Factor Is Required for Axonal Growth of Selective Groups of Neurons in the Arcuate Nucleus. Mol. Metab. 2015, 4, 471–482. [Google Scholar] [CrossRef]
  128. Yamamoto, M.; Sobue, G.; Yamamoto, K.; Terao, S.; Mitsuma, T. Expression of MRNAs for Neurotrophic Factors (NGF, BDNF, NT-3, and GDNF) and Their Receptors (P75NGFR, TrkA, TrkB, and TrkC) in the Adult Human Peripheral Nervous System and Nonneural Tissues. Neurochem. Res. 1996, 21, 929–938. [Google Scholar] [CrossRef]
  129. Donovan, M.J.; Miranda, R.C.; Kraemer, R.; McCaffrey, T.A.; Tessarollo, L.; Mahadeo, D.; Sharif, S.; Kaplan, D.R.; Tsoulfas, P.; Parada, L.; et al. Neurotrophin and Neurotrophin Receptors in Vascular Smooth Muscle Cells. Am. J. Pathol. 1995, 147, 309–324. [Google Scholar]
  130. Expression of neurotrophins in skeletal muscle: Quantitative comparison and significance for motoneuron survival and maintenance of function. J. Neurosci. Res. 1995, 42, 21–33. [CrossRef] [PubMed]
  131. Lommatzsch, M.; Braun, A.; Mannsfeldt, A.; Botchkarev, V.A.; Botchkareva, N.V.; Paus, R.; Fischer, A.; Lewin, G.R.; Renz, H. Abundant Production of Brain-Derived Neurotrophic Factor by Adult Visceral Epithelia. Implications for Paracrine and Target-Derived Neurotrophic Functions. Am. J. Pathol. 1999, 155, 1183–1193. [Google Scholar] [CrossRef] [PubMed]
  132. Cassiman, D.; Denef, C.; Desmet, V.J.; Roskams, T. Human and Rat Hepatic Stellate Cells Express Neurotrophins and Neurotrophin Receptors. Hepatology 2001, 33, 148–158. [Google Scholar] [CrossRef] [PubMed]
  133. Sornelli, F.; Fiore, M.; Chaldakov, G.N.; Aloe, L. Adipose Tissue-Derived Nerve Growth Factor and Brain-Derived Neurotrophic Factor: Results from Experimental Stress and Diabetes. Gen. Physiol. Biophys. 2009, 28, 179–183. [Google Scholar] [PubMed]
  134. Kharitonenkov, A.; Shiyanova, T.L.; Koester, A.; Ford, A.M.; Micanovic, R.; Galbreath, E.J.; Sandusky, G.E.; Hammond, L.J.; Moyers, J.S.; Owens, R.A.; et al. FGF-21 as a Novel Metabolic Regulator. J. Clin. Investig. 2005, 115, 1627–1635. [Google Scholar] [CrossRef] [PubMed]
  135. Teillon, S.; Calderon, G.A.; Rios, M. Diminished Diet-Induced Hyperglycemia and Dyslipidemia and Enhanced Expression of PPARalpha and FGF21 in Mice with Hepatic Ablation of Brain-Derived Neurotropic Factor. J. Endocrinol. 2010, 205, 37–47. [Google Scholar] [CrossRef] [PubMed]
  136. Genzer, Y.; Chapnik, N.; Froy, O. Effect of Brain-Derived Neurotrophic Factor (BDNF) on Hepatocyte Metabolism. Int. J. Biochem. Cell Biol. 2017, 88, 69–74. [Google Scholar] [CrossRef] [PubMed]
  137. Jung, U.J.; Choi, M.-S. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. Int. J. Mol. Sci. 2014, 15, 6184–6223. [Google Scholar] [CrossRef] [PubMed]
  138. Camerino, C.; Conte, E.; Cannone, M.; Caloiero, R.; Fonzino, A.; Tricarico, D. Nerve Growth Factor, Brain-Derived Neurotrophic Factor and Osteocalcin Gene Relationship in Energy Regulation, Bone Homeostasis and Reproductive Organs Analyzed by MRNA Quantitative Evaluation and Linear Correlation Analysis. Front. Physiol. 2016, 7, 456. [Google Scholar] [CrossRef] [PubMed]
  139. Yamanaka, M.; Itakura, Y.; Tsuchida, A.; Nakagawa, T.; Noguchi, H.; Taiji, M. Comparison of the Antidiabetic Effects of Brain-Derived Neurotrophic Factor and Thiazolidinediones in Obese Diabetic Mice. Diabetes Obes. Metab. 2007, 9, 879–888. [Google Scholar] [CrossRef]
  140. Matthews, V.B.; Aström, M.-B.; Chan, M.H.S.; Bruce, C.R.; Krabbe, K.S.; Prelovsek, O.; Akerström, T.; Yfanti, C.; Broholm, C.; Mortensen, O.H.; et al. Brain-Derived Neurotrophic Factor Is Produced by Skeletal Muscle Cells in Response to Contraction and Enhances Fat Oxidation via Activation of AMP-Activated Protein Kinase. Diabetologia 2009, 52, 1409–1418. [Google Scholar] [CrossRef]
  141. Suwa, M.; Yamamoto, K.-I.; Nakano, H.; Sasaki, H.; Radak, Z.; Kumagai, S. Brain-Derived Neurotrophic Factor Treatment Increases the SkeletalMuscle Glucose Transporter 4 Protein Expression in Mice. Physiol. Res. 2010, 59, 619–623. [Google Scholar] [CrossRef]
  142. Yang, X.; Brobst, D.; Chan, W.S.; Tse, M.C.L.; Herlea-Pana, O.; Ahuja, P.; Bi, X.; Zaw, A.M.; Kwong, Z.S.W.; Jia, W.; et al. Muscle-Generated BDNF Is a Sexually Dimorphic Myokine That Controls Metabolic Flexibility. Sci. Signal. 2019, 12, eaau1468. [Google Scholar] [CrossRef] [PubMed]
  143. Baeza-Raja, B.; Sachs, B.D.; Li, P.; Christian, F.; Vagena, E.; Davalos, D.; Le Moan, N.; Ryu, J.K.; Sikorski, S.L.; Chan, J.P.; et al. P75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep. 2016, 14, 255–268. [Google Scholar] [CrossRef] [PubMed]
  144. Sandrini, L.; Di Minno, A.; Amadio, P.; Ieraci, A.; Tremoli, E.; Barbieri, S.S. Association between Obesity and Circulating Brain-Derived Neurotrophic Factor (BDNF) Levels: Systematic Review of Literature and Meta-Analysis. Int. J. Mol. Sci. 2018, 19, 2281. [Google Scholar] [CrossRef] [PubMed]
  145. Beckers, S.; Peeters, A.; Zegers, D.; Mertens, I.; Van Gaal, L.; Van Hul, W. Association of the BDNF Val66Met Variation with Obesity in Women. Mol. Genet. Metab. 2008, 95, 110–112. [Google Scholar] [CrossRef] [PubMed]
  146. Shugart, Y.Y.; Chen, L.; Day, I.N.M.; Lewis, S.J.; Timpson, N.J.; Yuan, W.; Abdollahi, M.R.; Ring, S.M.; Ebrahim, S.; Golding, J.; et al. Two British Women Studies Replicated the Association between the Val66Met Polymorphism in the Brain-Derived Neurotrophic Factor (BDNF) and BMI. Eur. J. Hum. Genet. EJHG 2009, 17, 1050–1055. [Google Scholar] [CrossRef] [PubMed]
  147. Skledar, M.; Nikolac, M.; Dodig-Curkovic, K.; Curkovic, M.; Borovecki, F.; Pivac, N. Association between Brain-Derived Neurotrophic Factor Val66Met and Obesity in Children and Adolescents. Prog. Neuropsychopharmacol. Biol. Psychiatry 2012, 36, 136–140. [Google Scholar] [CrossRef] [PubMed]
  148. Xi, B.; Cheng, H.; Shen, Y.; Chandak, G.R.; Zhao, X.; Hou, D.; Wu, L.; Wang, X.; Mi, J. Study of 11 BMI-Associated Loci Identified in GWAS for Associations with Central Obesity in the Chinese Children. PLoS ONE 2013, 8, e56472. [Google Scholar] [CrossRef] [PubMed]
  149. Kalenda, A.; Landgraf, K.; Löffler, D.; Kovacs, P.; Kiess, W.; Körner, A. The BDNF Val66Met Polymorphism Is Associated with Lower BMI, Lower Postprandial Glucose Levels and Elevated Carbohydrate Intake in Children and Adolescents. Pediatr. Obes. 2018, 13, 159–167. [Google Scholar] [CrossRef] [PubMed]
  150. Vidović, V.; Maksimović, N.; Novaković, I.; Damnjanović, T.; Jekić, B.; Vidović, S.; Majkić Singh, N.; Stamenković-Radak, M.; Nikolić, D.; Marisavljević, D. Association of the Brain-Derived Neurotrophic Factor Val66Met Polymorphism with Body Mass Index, Fasting Glucose Levels and Lipid Status in Adolescents. Balk. J. Med. Genet. BJMG 2020, 23, 77–82. [Google Scholar] [CrossRef]
  151. Chen, S.-L.; Lee, S.-Y.; Chang, Y.-H.; Chen, S.-H.; Chu, C.-H.; Wang, T.-Y.; Chen, P.-S.; Lee, I.-H.; Yang, Y.-K.; Hong, J.-S.; et al. The BDNF Val66Met Polymorphism and Plasma Brain-Derived Neurotrophic Factor Levels in Han Chinese Patients with Bipolar Disorder and Schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 51, 99–104. [Google Scholar] [CrossRef]
  152. Mitra, S.; De, A.; Chowdhury, A. Epidemiology of Non-Alcoholic and Alcoholic Fatty Liver Diseases. Transl. Gastroenterol. Hepatol. 2020, 5, 16. [Google Scholar] [CrossRef]
  153. de Assis, G.G.; Hoffman, J.R.; Bojakowski, J.; Murawska-Ciałowicz, E.; Cięszczyk, P.; Gasanov, E.V. The Val66 and Met66 Alleles-Specific Expression of BDNF in Human Muscle and Their Metabolic Responsivity. Front. Mol. Neurosci. 2021, 14, 638176. [Google Scholar] [CrossRef] [PubMed]
  154. Rylander, M.; Brinton, J.T.; Sabel, A.L.; Mehler, P.S.; Gaudiani, J.L. A Comparison of the Metabolic Complications and Hospital Course of Severe Anorexia Nervosa by Binge-Purge and Restricting Subtypes. Eat. Disord. 2017, 25, 345–357. [Google Scholar] [CrossRef]
  155. Germain, N.; Galusca, B.; Grouselle, D.; Frere, D.; Billard, S.; Epelbaum, J.; Estour, B. Ghrelin and Obestatin Circadian Levels Differentiate Bingeing-Purging from Restrictive Anorexia Nervosa. J. Clin. Endocrinol. Metab. 2010, 95, 3057–3062. [Google Scholar] [CrossRef] [PubMed]
  156. Moreno-Encinas, A.; Sepúlveda, A.R.; Kurland, V.; Lacruz, T.; Nova, E.; Graell, M. Identifying Psychosocial and Familial Correlates and the Impact of the Stressful Life Events in the Onset of Anorexia Nervosa: Control-Case Study (ANOBAS): Psychosocial and Familial Correlates and Stressful Life Events in AN. Psychiatry Res. 2020, 284, 112768. [Google Scholar] [CrossRef]
  157. Polyakova, M.; Stuke, K.; Schuemberg, K.; Mueller, K.; Schoenknecht, P.; Schroeter, M.L. BDNF as a Biomarker for Successful Treatment of Mood Disorders: A Systematic & Quantitative Meta-Analysis. J. Affect. Disord. 2015, 174, 432–440. [Google Scholar] [CrossRef]
  158. Colle, R.; Trabado, S.; David, D.J.; Brailly-Tabard, S.; Hardy, P.; Falissard, B.; Fève, B.; Becquemont, L.; Verstuyft, C.; Corruble, E. Plasma BDNF Level in Major Depression: Biomarker of the Val66Met BDNF Polymorphism and of the Clinical Course in Met Carrier Patients. Neuropsychobiology 2017, 75, 39–45. [Google Scholar] [CrossRef]
  159. Dutt, R.; Shankar, N.; Srivastava, S.; Yadav, A.; Ahmed, R.S. Cardiac Autonomic Tone, Plasma BDNF Levels and Paroxetine Response in Newly Diagnosed Patients of Generalised Anxiety Disorder. Int. J. Psychiatry Clin. Pract. 2020, 24, 135–142. [Google Scholar] [CrossRef] [PubMed]
  160. Chu, L.; Sun, X.; Jia, X.; Li, D.; Gao, P.; Zhang, Y.; Li, J. The Relationship Among BDNF Val66Met Polymorphism, Plasma BDNF Level, and Trait Anxiety in Chinese Patients with Panic Disorder. Front. Psychiatry 2022, 13, 932235. [Google Scholar] [CrossRef]
  161. Cavaleri, D.; Moretti, F.; Bartoccetti, A.; Mauro, S.; Crocamo, C.; Carrà, G.; Bartoli, F. The Role of BDNF in Major Depressive Disorder, Related Clinical Features, and Antidepressant Treatment: Insight from Meta-Analyses. Neurosci. Biobehav. Rev. 2023, 149, 105159. [Google Scholar] [CrossRef]
  162. Duriez, P.; Ramoz, N.; Gorwood, P.; Viltart, O.; Tolle, V. A Metabolic Perspective on Reward Abnormalities in Anorexia Nervosa. Trends Endocrinol. Metab. 2019, 30, 915–928. [Google Scholar] [CrossRef] [PubMed]
  163. Tommasi, M.; Sergi, M.R.; Konstantinidou, F.; Franzago, M.; Pesce, M.; Fratta, I.L.; Grilli, A.; Stuppia, L.; Picconi, L.; Saggino, A.; et al. Association of COMT, BDNF and 5-HTT Functional Polymorphisms with Personality Characteristics. Front. Biosci. Landmark Ed. 2021, 26, 1064–1074. [Google Scholar] [CrossRef] [PubMed]
  164. Pauls, A.; Dimitropoulos, G.; Marcoux-Louie, G.; Singh, M.; Patten, S.B. Psychological Characteristics and Childhood Adversity of Adolescents with Atypical Anorexia Nervosa versus Anorexia Nervosa. Eat. Disord. 2022, 30, 210–222. [Google Scholar] [CrossRef] [PubMed]
  165. Katuri, R.B.; Gaur, G.S.; Sahoo, J.P.; Bobby, Z.; Shanmugavel, K. Association of Circulating Brain-Derived Neurotrophic Factor with Cognition among Adult Obese Population. J. Obes. Metab. Syndr. 2021, 30, 163–172. [Google Scholar] [CrossRef] [PubMed]
  166. Irani, H.; Abiri, B.; Khodami, B.; Yari, Z.; Lafzi Ghazi, M.; Hosseinzadeh, N.; Saidpour, A. Effect of Time Restricted Feeding on Anthropometric Measures, Eating Behavior, Stress, Serum Levels of BDNF and LBP in Overweight/Obese Women with Food Addiction: A Randomized Clinical Trial. Nutr. Neurosci. 2024, 27, 577–589. [Google Scholar] [CrossRef] [PubMed]
  167. Araya, A.V.; Orellana, X.; Espinoza, J. Evaluation of the Effect of Caloric Restriction on Serum BDNF in Overweight and Obese Subjects: Preliminary Evidences. Endocrine 2008, 33, 300–304. [Google Scholar] [CrossRef] [PubMed]
  168. Farinetti, A.; Aspesi, D.; Marraudino, M.; Marzola, E.; Amianto, F.; Abbate-Daga, G.; Gotti, S. Sexually Dimorphic Behavioral Effects of Maternal Separation in Anorexic Rats. Dev. Psychobiol. 2020, 62, 297–309. [Google Scholar] [CrossRef] [PubMed]
  169. Jiang, R.; Babyak, M.A.; Brummett, B.H.; Siegler, I.C.; Kuhn, C.M.; Williams, R.B. Brain-Derived Neurotrophic Factor (BDNF) Val66Met Polymorphism Interacts with Gender to Influence Cortisol Responses to Mental Stress. Psychoneuroendocrinology 2017, 79, 13–19. [Google Scholar] [CrossRef] [PubMed]
  170. Weisbrod, A.S.; Barry, E.S.; Graham, A.M.; Eklund, M.; Grunberg, N.E. Decreased BDNF in Female but Not Male Rats after Exposure to Stress: A Sex-Sensitive Rat Model of Stress? Stress 2019, 22, 581–591. [Google Scholar] [CrossRef]
  171. Ahuja, P.; Ng, C.F.; Pang, B.P.S.; Chan, W.S.; Tse, M.C.L.; Bi, X.; Kwan, H.-L.R.; Brobst, D.; Herlea-Pana, O.; Yang, X.; et al. Muscle-Generated BDNF (Brain Derived Neurotrophic Factor) Maintains Mitochondrial Quality Control in Female Mice. Autophagy 2022, 18, 1367–1384. [Google Scholar] [CrossRef]
  172. Nagata, J.M.; Vargas, R.; Sanders, A.E.; Stuart, E.; Downey, A.E.; Chaphekar, A.V.; Nguyen, A.; Ganson, K.T.; Buckelew, S.M.; Garber, A.K. Clinical Characteristics of Hospitalized Male Adolescents and Young Adults with Atypical Anorexia Nervosa. Int. J. Eat. Disord. 2024, 57, 1008–1019. [Google Scholar] [CrossRef]
  173. Murray, S.B.; Nagata, J.M.; Griffiths, S.; Calzo, J.P.; Brown, T.A.; Mitchison, D.; Blashill, A.J.; Mond, J.M. The Enigma of Male Eating Disorders: A Critical Review and Synthesis. Clin. Psychol. Rev. 2017, 57, 1–11. [Google Scholar] [CrossRef] [PubMed]
  174. Ridout, S.J.; Ridout, K.K.; Kole, J.; Fitzgerald, K.L.; Donaldson, A.A.; Alverson, B. Comparison of Eating Disorder Characteristics and Depression Comorbidity in Adolescent Males and Females: An Observational Study. Psychiatry Res. 2021, 296, 113650. [Google Scholar] [CrossRef]
  175. Ulfvebrand, S.; Birgegård, A.; Norring, C.; Högdahl, L.; von Hausswolff-Juhlin, Y. Psychiatric Comorbidity in Women and Men with Eating Disorders Results from a Large Clinical Database. Psychiatry Res. 2015, 230, 294–299. [Google Scholar] [CrossRef] [PubMed]
  176. Ribeiro, D.; Petrigna, L.; Pereira, F.C.; Muscella, A.; Bianco, A.; Tavares, P. The Impact of Physical Exercise on the Circulating Levels of BDNF and NT 4/5: A Review. Int. J. Mol. Sci. 2021, 22, 8814. [Google Scholar] [CrossRef] [PubMed]
  177. Rahmati, M.; Lee, S.; Yon, D.K.; Lee, S.W.; Udeh, R.; McEvoy, M.; Oh, H.; Butler, L.; Keyes, H.; Barnett, Y.; et al. Physical Activity and Prevention of Mental Health Complications: An Umbrella Review. Neurosci. Biobehav. Rev. 2024, 160, 105641. [Google Scholar] [CrossRef] [PubMed]
  178. Noetel, M.; Sanders, T.; Gallardo-Gómez, D.; Taylor, P.; del Pozo Cruz, B.; van den Hoek, D.; Smith, J.J.; Mahoney, J.; Spathis, J.; Moresi, M.; et al. Effect of Exercise for Depression: Systematic Review and Network Meta-Analysis of Randomised Controlled Trials. BMJ 2024, 384, e075847. [Google Scholar] [CrossRef]
  179. Pan, W.; Banks, W.A.; Fasold, M.B.; Bluth, J.; Kastin, A.J. Transport of Brain-Derived Neurotrophic Factor across the Blood–Brain Barrier. Neuropharmacology 1998, 37, 1553–1561. [Google Scholar] [CrossRef]
  180. Klein, A.B.; Williamson, R.; Santini, M.A.; Clemmensen, C.; Ettrup, A.; Rios, M.; Knudsen, G.M.; Aznar, S. Blood BDNF Concentrations Reflect Brain-Tissue BDNF Levels across Species. Int. J. Neuropsychopharmacol. 2011, 14, 347–353. [Google Scholar] [CrossRef]
  181. Elfving, B.; Plougmann, P.H.; Müller, H.K.; Mathé, A.A.; Rosenberg, R.; Wegener, G. Inverse Correlation of Brain and Blood BDNF Levels in a Genetic Rat Model of Depression. Int. J. Neuropsychopharmacol. 2010, 13, 563–572. [Google Scholar] [CrossRef]
  182. Cain, S.W.; Chang, A.-M.; Vlasac, I.; Tare, A.; Anderson, C.; Czeisler, C.A.; Saxena, R. Circadian Rhythms in Plasma Brain-Derived Neurotrophic Factor Differ in Men and Women. J. Biol. Rhythms 2017, 32, 75–82. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Multifaceted symptoms of anorexia nervosa.
Figure 1. Multifaceted symptoms of anorexia nervosa.
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Figure 2. Signaling Pathways of BDNF Protein. This figure illustrates the primary signaling pathways activated by BDNF binding to its receptors, TrkB and p75NTR. Upon mBDNF binding, TrkB receptors initiate downstream signaling cascades and promote neuronal survival, synaptic plasticity, synaptogenesis, and long-term potentiation (LTP). The interaction of pro-BDNF with its receptor p75NTR is involved in apoptosis, pruning and retraction of synaptogenesis, and long-term depression (LTD).
Figure 2. Signaling Pathways of BDNF Protein. This figure illustrates the primary signaling pathways activated by BDNF binding to its receptors, TrkB and p75NTR. Upon mBDNF binding, TrkB receptors initiate downstream signaling cascades and promote neuronal survival, synaptic plasticity, synaptogenesis, and long-term potentiation (LTP). The interaction of pro-BDNF with its receptor p75NTR is involved in apoptosis, pruning and retraction of synaptogenesis, and long-term depression (LTD).
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Figure 3. Influence of Val66Met polymorphism on molecular mechanisms and physiological outcomes related with AN. The molecular level effects of the Val66Met polymorphism include alterations in BDNF signaling towards p57 receptor, and a decrease in the availability of mBDNF. At the physiological level, human Met carriers are more likely to develop psychiatric vulnerabilities to environmental stress and metabolic diseases such as obesity. Certain influences of the Val66Met polymorphism exhibit sexual dimorphism. In the context of AN, Met alleles are currently of interest.
Figure 3. Influence of Val66Met polymorphism on molecular mechanisms and physiological outcomes related with AN. The molecular level effects of the Val66Met polymorphism include alterations in BDNF signaling towards p57 receptor, and a decrease in the availability of mBDNF. At the physiological level, human Met carriers are more likely to develop psychiatric vulnerabilities to environmental stress and metabolic diseases such as obesity. Certain influences of the Val66Met polymorphism exhibit sexual dimorphism. In the context of AN, Met alleles are currently of interest.
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Cao, J.; Gorwood, P.; Ramoz, N.; Viltart, O. The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder. Nutrients 2024, 16, 2617. https://doi.org/10.3390/nu16162617

AMA Style

Cao J, Gorwood P, Ramoz N, Viltart O. The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder. Nutrients. 2024; 16(16):2617. https://doi.org/10.3390/nu16162617

Chicago/Turabian Style

Cao, Jingxian, Philip Gorwood, Nicolas Ramoz, and Odile Viltart. 2024. "The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder" Nutrients 16, no. 16: 2617. https://doi.org/10.3390/nu16162617

APA Style

Cao, J., Gorwood, P., Ramoz, N., & Viltart, O. (2024). The Role of Central and Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker of Anorexia Nervosa Reconceptualized as a Metabo-Psychiatric Disorder. Nutrients, 16(16), 2617. https://doi.org/10.3390/nu16162617

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