Article

ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 713-732 © Pleiades Publishing, Ltd., 2026.

713

REVIEW

BDNF as a Mediator between Body Metabolism

and Brain Function in Health and Disease:

The Case of Alcohol Dependence

Danil I. Peregud

1,2,a

* and Nataliya V. Gulyaeva

2,3

Serbsky National Medical Research Center for Psychiatry and Narcology,

Ministry of Health of the Russian Federation, 119034 Moscow, Russia

Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences,

117485 Moscow, Russia

Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department,

115419 Moscow, Russia

e-mail: peregud_d@yahoo.com

Received March 14, 2026

Revised April 23, 2026

Accepted April 27, 2026

Abstract— Brain-derived neurotrophic factor (BDNF) is widely recognized as a critical molecule for the sur-

vival, growth, and maintenance of neurons in both the central and peripheral nervous systems, as well as

for the development of cognitive abilities and emotions. However, recent studies have shown that, in addition

to its role as a universal brain “fertilizer”, BDNF acts as a metabotrophin linking neuronal signaling with

systemic metabolism. BDNF serves as a key factor that integrates the body’s response to stress, physical

activity, and food intake with cellular mechanisms underlying neural plasticity and normal brain function.

The review presents evidence supporting BDNF as a bidirectionally metabolic “bridge”: body metabolism

controls BDNF production in the brain, while brain BDNF regulates body metabolism. Disruption of this

regulatory axis is associated with a broad range of neurological and somatic disorders, as well as their

comorbidities. Cellular mechanisms associated with disruptions in BDNF functions are explored in detail

through the example of alcohol dependence, a condition characterized by both impaired brain signaling

and somatic pathologies accompanied by metabolic changes.

DOI: 10.1134/S000629792660078X

Keywords: neurotrophic factor, BDNF, synaptic plasticity, stress, neurohumoral system, metabolism, energy

balance, alcohol dependence, brain, visceral systems, neuroendocrine mechanisms, brain diseases, neurode-

generative diseases, mental illnesses, somatic diseases, metabolic disturbances, comorbidity

* To whom correspondence should be addressed.

INTRODUCTION

Brain-derived neurotrophic factor (BDNF) is a

key member of the neurotrophin family, widely rec-

ognized for its essential role in the survival, growth,

and maintenance of neurons in both the central and

peripheral nervous systems. Accordingly, much of ex-

isting research has been focused on its neurotrophic

functions. However, BDNF exhibits a broad range of

biological activities in neural tissue across different

stages of ontogenesis. It supports the survival and dif-

ferentiation of neuronal stem – neuronal precursors

and synaptogenesis, promotes formation of neural net-

works, and participates in nerve impulse transmission

as a neuromodulator and neurotransmitter  [1]. This

apparent (and seemingly redundant) broad range of

BDNF functionals in the central nervous system (CNS)

and its principal involvement in the multilevel contin-

uum of brain plasticity and pathology  [2] are largely

determined by spatiotemporal factors, as particular

functions are associated with localization of molecular

processes at the level of individual neurons and larg-

er anatomical brain structures, as well as the dura-

tion of exposure to external or internal stimuli  [3,  4].

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Fig.  1. BDNF as a bidirectional metabolic bridge: body metabolism stimulates BDNF production in the brain, while brain

BDNF regulates body metabolism. In a state of active metabolism (physical activity, hunger), the body synthesizes specific

molecules (myokines, ketones, lactate) that enter the brain and activate BDNF gene transcription. This bottom-up signaling

pathways ensure the synthesis of additional BDNF. At the same time, BDNF produced in the brain modifies body metabolism

through the top-down signaling. For example, hypothalamic BDNF is a powerful regulator of the body’s energy homeostasis:

BDNF acts as a satiety signal in the hypothalamus and suppresses appetite (BDNF deficiency leads to overeating and obesity),

regulates insulin sensitivity (increases it in muscles and liver), and promotes utilization of lipids (activates the sympathetic

nervous system, thus stimulating lipid and fatty acid catabolism in brown fat for heat production). BDNF’s role as an “energy

status inspector” involves the control of carbohydrate and lipid metabolism efficiency through promotion of mitochondri-

al biogenesis and regulation of 5′-AMP-activated protein kinase, a key enzyme in the control of cellular energy balance.

The metabolic control of synaptic transmission by BDNF is primarily aimed at ensuring an adequate energy supply for

synaptic function, particularly via mitochondrial biogenesis, control of AMPA receptors on the postsynaptic membrane, and

the maintenance of balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitter systems. Additionally,

BDNF protects neurons from excitotoxicity and oxidative stress by upregulating antioxidant defense enzymes. Disruption of

this bidirectional system establishes a vicious cycle in various pathologies (including those accompanied by chronic stress

and obesity), where high cortisol levels and systemic inflammation suppress BDNF expression, while low BDNF levels lead

to impaired appetite control and increased insulin resistance, further exacerbating inflammation and neuroinflammation.

In recent years, BDNF has been increasingly rec-

ognized not only as a general neurotrophic support

factor (“fertilizer”), but also as a metabotrophin that

links neuronal signaling with systemic metabolism. In

this capacity, BDNF integrates the body’s responses to

physical activity, energy consumption, stress, and oth-

er factors with the cellular mechanisms underlying

neuroplasticity and normal brain function. Indeed,

BDNF regulates basic metabolic processes in and be-

yond the brain. It influences food intake by stimu-

lating the corresponding center in the ventromedial

hypothalamus, modulates insulin sensitivity through

its secretion by pancreatic β-cells, and contributes

to energy homeostasis by regulating fatty acid and

carbohydrate metabolism in the liver, adipose tissue,

and muscles  [5-7]. Dysregulation of BDNF activity

is associated with metabolic dysfunction in somat-

ic organs and corresponding clinical manifestations,

which, given the pleiotropy of BDNF action, may be

associated with the development of various brain pa-

thologies  [8,  9].

The main objective of this review was to sum-

marize evidence supporting the dual role of BDNF in

regulating both the CNS function and systemic me-

tabolism. We propose a concept of BDNF as a crucial

metabolic bridge that operates bidirectionally: body

metabolism stimulates BDNF production in the brain,

while brain BDNF regulates body metabolism (Fig.  1).

As an example of a disruption of this regulatory axis,

we examined the role of BDNF in the development

of alcohol dependence, a condition characterized by

both impaired brain signaling and the development

of somatic pathologies associated with metabolic

changes.

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BDNF COORDINATES BRAIN FUNCTIONS

AND BODY METABOLISM

BDNF is a pleiotropic neurotrophin that exerts

diverse effects on metabolism, intracellular signaling,

neuronal morphology, and synaptic plasticity – pro-

cesses fundamental to neural circuit formation and

cognitive functions. Its activity is tightly controlled

and diversified by multiple molecular and cellular

mechanisms, including the transport and subcellu-

lar localization of distinct BDNF mRNA isoforms,

pre- and postsynaptic release, interactions with the

tropomyosin-related receptor kinase (TrkB), and pro-

teolytic conversion of proBDNF into mature BDNF

and BDNF propeptide  [10]. Like other neurotrophins,

BDNF signals primarily through specific TrkB pro-

teins, but also binds to the low-affinity p75 neurotro-

phin receptor (p75NTR), triggering distinct signaling

cascades. Mature BDNF is a potent neurotrophin that

promotes neuronal survival and differentiation, while

its precursor, proBDNF, exerts opposing effects by fa-

cilitating apoptosis and neuronal death. At the mo-

lecular level, BDNF–TrkB signaling triggers survival

pathways, such as phosphoinositide 3-kinase (PI3K)/

protein kinase  B (AKT) and mitogen-activated pro-

tein kinase (MAPK)/extracellular signal-regulated ki-

nases (ERK) cascade. In contrast, proBDNF activates

p75NTR and sortilin, thereby inducing neuronal apop-

tosis through the JNK (Jun N-terminal kinase), RhoA

(Ras homolog gene family member  A), NF-κB (nuclear

factor kappa  B), and Rac-GTPase pathways, leading to

caspase activation and mitochondrial dysfunction  [11].

Disruption of the balance between BDNF and proBD-

NF due to cellular damage, stress, or altered signaling

is implicated in apoptosis-related neurodegenerative

disorders, such as Alzheimer’s, Parkinson’s, and Hun-

tington’s diseases.

BDNF is synthesized and stored in the presyn-

aptic terminals of excitatory neurons along with its

propeptide. Neuronal activation not only triggers

release of both peptides but also upregulates BDNF

transcription  [12]. The interplay between BDNF sig-

naling and excitatory glutamatergic system is essen-

tial for synaptic and cellular plasticity  [13,  14] and

creates a bidirectional regulatory network that pro-

vides their mutual regulation. Available data suggest

that complex and properly coordinated connections

between the two systems ensure optimal synaptic and

cellular plasticity in the normal brain  [15], and their

disruption contributes to impaired plasticity and the

pathophysiology of depressive and other affective dis-

orders. The central role of BDNF in synaptic plasticity

underlies its involvement in learning, memory, and

cognitive functions. Consequently, disturbances in

BDNF signaling are associated with a broad spectrum

of neurological, psychiatric, and somatic diseases.

BDNF’s role in neuroplasticity. The brain re-

tains a remarkable lifelong capacity for structural and

functional reorganization. This fundamental mecha-

nism of adaptive neuroplasticity supports brain’s abil-

ity to perform effective cognitive functions despite

increased vulnerability of neurons upon aging or

under adverse conditions  [16]. The neurotrophin sys-

tem is affected by aging, and changes in BDNF expres-

sion correlate with age-related alterations in brain

structure and function. BDNF regulates the number,

structure, and plasticity of dendritic spines through

two functionally antagonistic receptors, TrkB and

p75NTR  [17]. In the hippocampus, disruptions of these

regulatory mechanisms affect dendritic spine forma-

tion, alter the morphology of pyramidal neurons, and

impair synaptic integration of newborn granule cells

into existing circuits in the mature hippocampus, ul-

timately compromising cognitive performance  [18].

Many of synaptic effects of BDNF are mediated by

the TrkB-dependent stimulation of local protein syn-

thesis in both presynaptic and postsynaptic compart-

ments. This localized protein synthesis is critical for

various stages of neuronal development, including

neurite outgrowth, synapse formation, and long-term

stabilization, making its regulation by BDNF–TrkB sig-

naling a fundamental mechanism for the formation of

the structure and functions of developing and mature

neural networks  [19].

While BDNF’s neuronal functions are well char-

acterized, its effects on astrocytes are less understood.

Recently, it has been shown that astrocytes actively

participate in BDNF signaling. Binding of extracellu-

lar BDNF, including BDNF released from synapses, to

astrocytic TrkB activates intracellular responses that

vary significantly depending on the brain region,

developmental stage, and expressed receptors  [20].

BDNF deficiency in astrocytes, similar to neurons, has

been found in certain neuropathological conditions.

Beyond the CNS, BDNF coordinates development

of organism by controlling and integrating genetic,

metabolic, and environmental signals through par-

ticipation in complex neuroendocrine networks. For

example, BDNF plays a key role in hypothalamic

maturation and plasticity, activation of gonadotro-

pin-releasing hormone neurons, and integration of

metabolic and environmental cues related to repro-

ductive development  [21]. Hypothalamic BDNF reg-

ulates energy metabolism in a sex-specific manner,

thus contributing to sexually dimorphic metabolic

control  [22].

BDNF interactions with the neurohumoral

system, stress, and inflammation. Involvement of

BDNF in the regulatory functions in the brain and

entire body crucially depends on its interaction with

the neuroendocrine system, particularly, the hypo-

thalamic–pituitary–adrenal (HPA) axis. As the brain’s

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primary neurotrophin, BDNF selectively activates

TrkB, exerting multimodal effects on neurodevelop-

ment, synaptic plasticity, cellular integrity, and neural

network dynamics. In parallel, glucocorticoids (GCs),

steroid hormones released by the adrenal glands,

cross the blood–brain barrier and bind to their re-

ceptors, modulating genomic, epigenomic, and post-

genomic events. GC signaling in neural tissue contrib-

utes to neurodevelopment, synaptic plasticity, cellular

homeostasis, cognition, and emotional responses  [23].

Recent studies have shown that these two major in-

tegrative regulatory systems interact at various levels,

sharing common intracellular pathways. The regula-

tion of BDNF expression by GCs depends on a con-

text, while BDNF can counteract the effects of GCs

on long-term potentiation, neurite growth, and cell

death. At the same time, GCs regulate intraneuronal

transport and lysosomal degradation of BDNF  [24].

Inthe hippocampus, GCs help coordinate the function-

ing of multiple components and mechanisms of neu-

ral plasticity, including BDNF signaling, neurogenesis,

glutamatergic neurotransmission, activity of microglia

and astrocytes, neuroinflammation, protease activi-

ty, metabolic hormones, and neurosteroids [23, 25].

Although most studies have been focused on BDNF

and GC interactions in neurons, emerging evidence

suggests that these interactions may also play a sig-

nificant role in non-neuronal cells, particularly as-

trocytes. Elucidating the temporal and spatial aspects

of specific neurobiological mechanisms underlying

interactions between BDNF and GCs is crucial for un-

derstanding brain function in health and disease, in-

cluding neurodegenerative/neuroinflammatory pathol-

ogies, as well as cognitive and affective disorders  [24].

In addition to its many roles in the CNS, BDNF is

involved in shaping body’s stress responses. It influ-

ences behavioral reactions associated with the brain

limbic system, endocrine system, and HPA axis stim-

ulation. Although many stressors increase HPA axis

activity, neuronal responses to this activation vary

considerably. These differences likely reflect the in-

volvement of distinct neuromediator pathways, neu-

romodulators, neurohormones, and stress-induced

changes in gene expression  [26]. Both the synthesis

and secretion of BDNF are modulated by stress, with

outcomes depending on factors such as the stressor

type, and duration of the stress, the time of neurotro-

phin detection, brain region, individual resilience to

stress, and genetic background.

Chronic stress, as a major environmental fac-

tor, has drawn increasing attention due to its link to

BDNF dysregulation and neuroinflammation. From

this perspective, it is understandable why proposed

diagnostic biomarkers of chronic stress include cor-

tisol, adrenocorticotropic hormone (ACTH), catechol-

amines, glucose, triglycerides, prolactin, oxytocin, de-

hydroepiandrosterone sulfate, C-reactive protein, and

interleukins-6 and 8, alongside BDNF  [27]. Chronic

stress activates both central and peripheral signaling

through the HPA axis stimulation and disruption of

the gut microbiota  [28]. In the CNS, stress promotes

polarization of microglia toward a pro-inflammatory

(M1-like) phenotype. These cells release factors such

as interleukin-1α, tumor necrosis factor-α, and com-

plement component C1q, which induce astrocytes to

adopt a neurotoxic (A1-like) state, forming the so-

called M1–A1 axis. This axis contributes to the disrup-

tion of BDNF regulation through several mechanisms:

released pro-inflammatory cytokines suppress BDNF

transcription and translation; impaired lactate metab-

olism in astrocytes reduces energy supply to neurons

and acidifies the microenvironment, further amplify-

ing inflammation and downregulating BDNF expres-

sion; disruption of the blood–brain barrier permits

infiltration to the brain of peripheral immune cells

that work synergistically with glial cells to exacerbate

neuroinflammation  [28]. Reduced BDNF levels, along

with the imbalance between its precursor and mature

forms, ultimately lead to impaired synaptic plasticity

in brain regions such as the hippocampus and amyg-

dala, provoking anxiety-like behavior.

The chronic unpredictable mild stress (CUMS)

paradigm is a widely used preclinical model for

studying the pathophysiology of stress-induced neuro-

psychiatric disorders. Persistent HPA axis stimulation

leads to hypercortisolemia, insulin resistance, and

impaired neuroplasticity driven by dysregulation of

BDNF–TrkB signaling, oxidative stress, and activation

of inflammatory pathways  [29].

BDNF, EATING BEHAVIOR,

AND ENERGY BALANCE

Increasing evidence points to BDNF as a pleio-

tropic signaling molecule that plays a central role

in regulating energy balance both in the brain and

throughout the entire body. BDNF and its receptors

are widely expressed in the hypothalamus, where pe-

ripheral signals related to feeding control and meta-

bolic activation are integrated to generate anorexigen-

ic and orexigenic responses  [30]. BDNF coordinates

adaptive responses to fluctuations in energy intake

and expenditure, linking the CNS with peripheral tis-

sues, such as muscles, liver, and adipose tissue, into

a highly integrated operational network. Physiological

and molecular mechanisms mediated by BDNF are in-

volved in processes essential for energy metabolism,

including control of mitochondrial function and dy-

namics, thermogenesis, physical exercise-induced cog-

nitive effects, insulin sensitivity, and cellular glucose

transport.

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Disruption of CNS regulation and homeostatic

pathways controlling energy metabolism in peripher-

al tissues leads to the development of metabolic dis-

orders. Maintaining energy balance requires neural

circuits to integrate both direct and feedback signals

from the internal metabolic environment to appro-

priately regulate food intake and energy expenditure.

BDNF signaling through TrkB and p75NTR plays a

critical in sustaining the overall energy homeostasis

of the body  [6]. Extensive evidence from both human

and rodent studies demonstrates that BDNF is a key

regulator of feeding behavior, energy expenditure,

and glycemic control. It modulates both homeostatic

and hedonic feeding and influences energy expen-

diture via hypothalamus, dorsal vagal complex, and

mesolimbic dopamine reward system  [31]. Because

metabolic circuits are inherently plastic and adapt to

the body’s energy demands, it is not surprising that

BDNF, an established regulator of synaptic plasticity,

plays such an important role in coordinating brain

and whole-body metabolism. Considering its well-

known functions in providing structural plasticity in

the hippocampus and neocortex, BDNF likely drives

the reorganization of feeding-related neural circuits

in response to metabolic signals, thereby supporting

optimal energy balance. This concept is corroborated

by studies in the ventromedial hypothalamus show-

ing that both neuronal and astrocytic components of

metabolic excitatory circuits undergo BDNF-depen-

dent adaptations to changes in caloric intake  [32].

Given its role in regulating local protein synthesis in

synapses, BDNF may facilitate rapid, postprandial re-

modeling of the synaptic proteome in neurons that

control feeding, energy expenditure, and glucose mo-

bilization  [33,  34].

In the context of BDNF as a key factor linking

metabolism and brain information function, its role

in regulating eating behavior becomes particularly

important. The discovery of BDNF-expressing neurons

in the paraventricular hypothalamus, a region critical

for the regulation of energy intake, physical activity,

and thermogenesis, provides strong evidence of BD-

NF’s involvement in eating behavior. However, effects

of BDNF are complex and sometimes paradoxical, as

they vary depending on its molecular form (mature

BDNF, pro-BDNF, or its pro-domain) and specific brain

region in which it acts  [35]. Food-related reward stim-

uli induce BDNF expression and release in the hypo-

thalamus, contributing to appetite suppression and the

promotion of satiety. In reward-related regions, such

as the ventral tegmental area, nucleus accumbens,

and dorsal striatum, BDNF modulates the motiva-

tional and hedonic aspects of feeding. Meanwhile,

in the prefrontal cortex and hippocampus, BDNF in-

fluences executive function, learning, and memory,

thereby shaping decision-making and behavioral re-

sponses to food-related cues. Chronic consumption of

high-calorie food causes long-term changes in BDNF

expression and release, which, together with changes

in other neurobiological factors, may alter appetite

patterns and hedonic responses  [31].

The gut–brain axis has recently emerged as a cen-

tral integrative system influencing both neurophys-

iological and cognitive processes. This bidirectional

communication network integrates neural, immune,

and metabolic signaling, and its dysregulation is im-

plicated in the development of gastrointestinal, met-

abolic, neurological, and psychiatric disorders  [36].

The gut microbiota modulates neurotrophic factors,

including BDNF. Within this axis, BDNF contributes

to maintaining intestinal barrier integrity and regu-

lating immune and inflammatory responses  [37].

BDNF is also closely associated with intestine-pro-

duced incretin hormones, particularly glucagon-like

peptide-1 (GLP-1), which stimulates insulin secretion

after meals before blood sugar levels rise significant-

ly. GLP-1 receptors in the brain control food intake

and body weight  [38]. Activation of GLP-1 receptors

in neurons, microglia, and astrocytes triggers neu-

roprotective pathways, leading to increased BDNF

synthesis, enhanced neurogenesis, anti-inflammatory

effects, reduction of oxidative stress and mitochon-

drial dysfunction, inhibition of apoptosis, improved

neuronal insulin sensitivity, and stimulation of cellu-

lar energy metabolism. These processes are further

supported by functional improvements in autophagy

and mitophagy  [39]. Such effects have formed the ba-

sis for the therapeutic use of GLP-1 receptor agonists

not only in metabolic disorders, such as metabolic

syndrome and type  2 diabetes, but for the correction

of brain disorders, including neurodegenerative dis-

eases  [40]. It has been shown that GLP-1 and BDNF

jointly control local protein synthesis in synapses in-

volved in appetite control  [34].

BDNF, BRAIN DISEASES, METABOLIC DISEASES,

AND THEIR COMORBIDITY

BDNF is the primary neurotrophin, and disrup-

tion of its functional activity is strongly associat-

ed with the pathogenesis of progressive neurologi-

cal and psychiatric disorders. Indeed, alterations in

BDNF–TrkB signaling are recognized as key molecular

mechanisms underlying cognitive decline and affec-

tive disorders. The BDNF gene comprises nine exons

in rodents and eleven in humans. Each exon is con-

trolled by a unique promoter, leading to the expres-

sion of exon-specific transcripts. Although only one

exon is protein-coding, alternative mRNA variants en-

code an identical preproprotein amino acid sequence.

These transcripts exhibit region-specific expression

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and are differentially regulated under various phys-

iological conditions, suggesting distinct cellular and

functional roles. Specific BDNF transcripts driven by

particular promoters have been implicated in psychi-

atric disorders, including schizophrenia, anxiety dis-

orders, and cognitive deficits  [41]. In addition, poly-

morphisms in genes encoding BDNF or its receptors

have been linked to an increased risk of developing

neuropathologies  [42,  43], including mental illness-

es resulting from the use of psychoactive substanc-

es  [44,  45].

Recent studies further highlight a connection be-

tween dysregulated TrkB signaling and chronic stress.

Chronic stress is a well-established contributor to the

development of both psychiatric and neurological

disorders, including various forms of dementia  [46].

According to the neuronal atrophy hypothesis, pro-

longed stress induces structural and functional alter-

ations in critical brain regions through several inter-

connected mechanisms. These include impaired BDNF

regulation leading to reduced BDNF–TrkB signaling,

stress-related elevation of GC levels, cytokine-driv-

en neuroinflammation, and mitochondrial dysfunc-

tion that disrupts neuronal energy metabolism  [47].

Together, these processes compromise synaptic plas-

ticity, exacerbate structural atrophy, and contribute to

persistent cognitive and mental deficits  [46]. Current

data not only demonstrate a close link between the

BDNF–TrkB signaling and the development of cogni-

tive impairments in stress-associated disorders, but

also suggest the therapeutic potential of strategies

aimed at enhancing BDNF–TrkB signaling in brain

disorders.

Over the past two decades, inflammatory disor-

ders have become a central paradigm in understand-

ing the pathogenesis of mental illnesses. Individuals

with a range of mental disorders frequently exhibit

low-grade systemic inflammation, while alterations

in gut microbiota and disruptions of the blood–brain

barrier represent key mechanisms through which

peripheral immune activity influences brain function

[48,  49]. Identified interactions between BDNF and

inflammatory pathways further highlight the role of

this neurotrophin in the immunopathophysiology of

mental illnesses. At the intracellular level, receptor

activation converges on major signaling hubs, includ-

ing NF-κB, JAK (Janus kinase)/STAT (signal transducer

and activator of transcription), and MAPK cascades,

while the NLRP3 (NLR family pyrin domain contain-

ing3) inflammasome links mitochondrial dysfunction

and oxidative stress to interleukin-1β release and

pyroptosis. These processes lead to dysregulation of

glial cells, changes in BDNF–TrkB signaling, and alter-

ations in the kynurenine pathway, contributing to ex-

citotoxicity and synaptic deficits  [48]. BDNF’s involve-

ment in immune responses along with its interaction

with neuroprotective and cell adhesion-related differ-

entially expressed proteins (DEPs), is considered as

a conserved regulatory mechanism protecting against

the damaging effects of excessive immune system ac-

tivation and hyperinflammation, including neurotox-

icity  [49]. Conversely, reduced BDNF levels commonly

observed in mood disorders and other mental illness-

es (e.g., schizophrenia), are associated with impaired

neurotrophic signaling and activation of inflammato-

ry pathways, leading to neurotoxicity, and potential

interaction with reduced expression of other DEPs

[catenin CTNNB1, cadherin CDH1, or DISC1 (disrupted

in schizophrenia  1)], resulting in widespread synaptic

and axonal dysfunction.

A substantial body of evidence supports BDNF as

a key mediator of antidepressant effects, with thera-

peutic efficacy typically associated with a registered

BDNF response. For instance, patients who respond to

ketamine treatment typically show significant eleva-

tions in BDNF compared to baseline, whereas non-re-

sponders do not exhibit such changes  [50]. The con-

tinuum sorting hypothesis proposes that both BDNF/

proBDNF and BDNF propeptide act as critical mod-

ulators that fine-tune antidepressant-induced neuro-

plasticity in specific brain regions, thereby shaping

behavioral responses to stress  [51]. Importantly, re-

gion-specific variations in BDNF–TrkB signaling can

produce distinct functional outcomes and may un-

derlie diverse pathological processes, all of which are

closely tied to metabolic alterations. For example, in

the amygdala, BDNF activity provides a mechanistic

link between metabolic changes associated with man-

ifestation of anxiety-related behaviors  [34].

Recent studies consistently link disrupted BDNF

signaling to the onset and progression of neurode-

generative disorders. Proposed central mechanism

include the regulation of energy homeostasis, mito-

chondrial biogenesis and dynamics, and other mito-

chondrial processes vital for synaptic transmission

and plasticity modulated by the BDNF-TrkB signaling

pathway  [52]. In particular, the BDNF–TrkB–protein

kinase  A (PKA) signaling cascade, operating in both

the cytosol and mitochondria, plays a critical role in

mitochondrial transport, distribution, and content,

thereby ensuring that synapses meet their high ener-

gy demands. Dysregulation of this pathway is strongly

associated with neurodegenerative disorders such as

Alzheimer’s and Parkinson’s diseases, both of which

are characterized by mitochondrial dysfunction and

reduced BDNF expression  [53]. For example, in Par-

kinson’s disease, diminished BDNF–TrkB signaling

correlates with disease severity and long-term com-

plications, while its activation through targeted inter-

ventions has been shown to alleviate neuropatholog-

ical features  [54]. These findings suggest that BDNF

may serve a dual role in Parkinson’s disease, acting

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

both as a neuroprotective factor and as a modulator

of dopaminergic neuron function  [55].

Beyond the CNS, BDNF is widely expressed in

peripheral tissues, including the pancreas, intestine,

and skeletal muscle. Alterations in BDNF signaling

are increasingly implicated in metabolic disorders,

such as diabetes and metabolic syndrome, which of-

ten co-occur with neurological complications. BDNF

is thought to contribute to the neuropathophysiology

of brain damage, particularly, cognitive impairment

observed in type  2 diabetes  [56]. In diabetes, acti-

vation of the BDNF–TrkB–CREB (cAMP response ele-

ment-binding protein) cascade suppresses hepatic glu-

coneogenesis, reduces insulin resistance by enhancing

insulin signaling in the liver, and protects pancreatic

β-cells from degeneration  [57]. Individuals with dia-

betes or impaired glycemic control have lower circu-

lating BDNF levels than healthy controls  [58]. Serum

BDNF levels are decreased in patients with diabetes,

depression, and those with these comorbid conditions

compared to the control group  [57]. Reduced BDNF

levels may impair glucose metabolism and contribute

to the pathogenesis of diabetes and associated com-

plications.

A compelling illustration of BDNF’s role in the

comorbidity of somatic and neurological disorders is

the association between sarcopenic obesity and Alz-

heimer’s disease  [59]. In Alzheimer’s disease, reduced

BDNF signaling through its receptor contributes to the

activation of glycogen synthase kinase  3β (GSK3β),

promoting beta-amyloid production and formation of

amyloid plaques, as well as tau protein hyperphos-

phorylation and formation of neurofibrillary tangles.

In skeletal muscles, lower BDNF concentrations are

associated with impaired recovery and regeneration

of muscle fibers, increasing the likelihood of sarcope-

nia. BDNF deficiency impairs mitochondrial function,

leading to insulin resistance and increased adipose

tissue mass. BDNF concentration negatively correlates

with markers of obesity, linking reduced BDNF to

weight gain. Enhancing BDNF production may there-

fore simultaneously mitigate Alzheimer’s disease pa-

thology, improve mitochondrial function in skeletal

muscle, reduce insulin resistance, and promote the

formation of brown adipose tissue  [59].

Taken together, these findings highlight BDNF

as a key integrator of brain function and systemic

metabolism in both physiological and pathological

conditions. This relationship suggests that metabol-

ic disorders can trigger neurological disease, while

neurodegenerative and psychiatric conditions can, in

turn, contribute to the development of metabolic dis-

eases by disrupting the overall metabolic control by

the brain. In this context, BDNF sits at the center of

a self-reinforcing vicious cycle of comorbidities affect-

ing both brain and body. Therapeutic strategies that

target shared underlying mechanisms are therefore

particularly promising. One notable example is the

use of GLP-1 receptor agonists, widely prescribed for

type  2 diabetes and obesity, which have demonstrat-

ed significant neuroprotective potential  [40]. These

agents consistently enhance BDNF expression and

signaling across various models of diabetes, neuro-

degeneration, and neurotoxicity. Elevated BDNF lev-

els are associated with improved synaptic plasticity,

enhanced cognitive performance, and increased neu-

ronal survival  [60]. Clinical studies corroborate these

findings, thus confirming the central role of BDNF

in mediating the neuroprotective effects of incre-

tin-based therapies.

BDNF, PHYSICAL ACTIVITY, NUTRITION,

AND SYSTEMIC METABOLISM

Physical exercise and fasting regulate appetite,

increase energy efficiency, increase the number of

brown fat cells, and promote weight loss through ac-

tivation of hypothalamic neurons. In addition, both

interventions influence brain plasticity and cognitive

function by elevating BDNF levels, reducing oxidative

stress and mitochondrial dysfunction in neural tissue,

and thereby potentially lowering the risk of brain dis-

eases  [61,  62]. The effect of physical exercise is one of

the most studied examples of organ–brain communi-

cation, in which peripheral organs can interact with

the CNS, particularly the hippocampus, and mediate

structural and functional changes in brain structures.

Physical exercise stimulates BDNF signaling, mod-

ulates monoaminergic (serotonergic, dopaminergic,

noradrenergic) systems, regulates inflammatory and

oxidative stress pathways, and promotes neurogene-

sis and synaptic plasticity  [63].

Recently, there has been growing interest in exer-

cise-induced signaling molecules (metabolites, growth

factors, cytokines, and hormones) collectively termed

exerkines, which help explain systemic communica-

tions between metabolically active organs and the

brain during and after physical activity. Exerkines en-

compass a broad range of signaling factors released

in response to exercise, such as BDNF, oxylipins, ad-

iponectin, lactate, reactive oxygen species, including

lipid peroxidation products, and cytokines, e.g., inter-

leukin-6  [64]. These molecules can exert acute, short-

term, or long-term effects that support whole-body

energy homeostasis and brain function. Exerkines are

produced by multiple tissues, including skeletal mus-

cle, liver, adipose tissue, kidney, adrenal glands, and

circulating cells. They collectively regulate metabolic

processes, energy utilization, and neural activity and

control fundamental brain functions such as learning

and memory, neurogenesis, cell proliferation, dendritic

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remodeling, and synaptic plasticity, often through

modulation of the BDNF pathway  [65]. Myokines are

often considered a distinct subset of exerkines. These

muscle-derived signaling proteins, which include

BDNF, irisin, and interleukin-6, promote neuronal

survival and synaptic plasticity. By initiating myokine

production, physical exercise promotes mitochondrial

biogenesis and oxidative capacity of skeletal muscles

through the AMPK (AMP-activated protein kinase)–

PGC-1α (peroxisome proliferative activated receptor

gamma coactivator) signaling pathway, restoring fatty

acid oxidation and glucose metabolism.

At the molecular level, BDNF acts as a key me-

diator of the beneficial effects of physical exercise

on the brain. Exercise reliably increases BDNF levels

in the brain, thereby promoting neuroplasticity and

enhancing cognitive function  [66,  67]. The principal

mechanisms underlying exercise-induced BDNF up-

regulation include activity-dependent neuronal ex-

pression, increased cerebral blood flow (the hemo-

dynamic hypothesis), and signaling from peripheral

tissues via myokines and other exerkines (the humor-

al hypothesis)  [68]. In a rodent model of traumatic

brain injury, physical training reduced reactive oxy-

gen species levels in the hippocampus and decreased

microglial reactivity, pro-inflammatory cytokine lev-

els, and caspase-3 activity, while simultaneously in-

creasing the overall antioxidant activity and the ex-

pression of anti-apoptotic factors. These changes were

accompanied by upregulation of BDNF and compo-

nents of its signaling cascade (TrkB and synapsin-1)

and activation of electron transport chain, collective-

ly promoting neurogenesis  [69]. Functionally, physical

exercise improved cognitive functions, spatial learn-

ing and memory, and reduced anxiety-like behaviors.

In other experiments, as well as in human studies,

exercise-induced increase in BDNF levels correlate

with enhanced neuroplasticity, improved mood, and

reduced anxiety symptoms  [70].

Dietary interventions, such as caloric restriction

and intermittent fasting, also promote BDNF expres-

sion and neuroprotective signaling, which regulates

stress-related chaperones and supports cognitive

function  [71,  72]. The ketogenic diet, in particular,

has been shown to enhance cognitive function and

slow the progression of experimental neuropathol-

ogies by increasing BDNF expression, reducing oxi-

dative stress, stimulating mitochondrial biogenesis,

and activating autophagy  [73]. Intermittent fasting is

likewise associated with reduced neuroinflammation

and increased BDNF levels, thereby supporting brain

plasticity in response to reward-related stimuli  [74].

It also enhances hippocampal neurogenesis and syn-

aptic plasticity via BDNF- and CREB-dependent sig-

naling pathways  [75]. By modulating the gut–brain

axis, reshaping the gut microbiota, promoting ketone

body production, reprogramming cellular bioenerget-

ics and related metabolic pathways, and participating

in stress adaptation mechanisms, intermittent fasting

promotes BDNF induction. This, in turn, optimizes

mitochondrial biogenesis, autophagy, and neuroin-

flammation  [76]. Preclinical and clinical evidence in-

dicates that intermittent fasting can improve synap-

tic plasticity and integrity, reduce proteotoxic stress,

and help restore glial and immune balance in models

of neurodegenerative disorders such as Alzheimer’s,

Parkinson’s, and Huntington’s diseases, and amyo-

trophic lateral sclerosis, with BDNF being the prima-

ry molecular mediator of these effects  [77]. Moreover,

intermittent fasting shows promise as a therapeutic

strategy for affective disorders, including depression.

Its beneficial influence on BDNF levels, tryptophan

metabolism, inflammatory pathways, HPA axis, and

the gut–brain axis highlights its potential in this con-

text  [78].

INVOLVEMENT OF BDNF IN THE PATHOGENESIS

OF ALCOHOL DEPENDENCE

Uncontrolled chronic alcohol consumption, char-

acterized by the development of dependence, rep-

resents a complex pathological state in which clin-

ical features associated with a broad spectrum of

CNS disorders may emerge at different stages of its

progression. These include epileptogenesis, periph-

eral neuropathies, cognitive impairment, and psy-

chotic and affective disorders. Beyond the formation

of dependence itself, long-term ethanol exposure is

accompanied by disruptions in energy metabolism,

development of oxidative stress, and inflammatory

responses at the systemic level, which can manifest

as gastrointestinal diseases, liver damage, type  2 dia-

betes, obesity, and cardiovascular diseases  [79].

The complex nature of alcohol-related disorders

is determined by a wide range of molecular mecha-

nisms and factors. In this context, particular attention

is given to neurotrophins (e.g., BDNF) which plays a

key role in the molecular pathways underlying the

effects of alcohol and the development of dependence

[80-82]. A simplified model of alcohol dependence

posits that reduced BDNF levels, together with neu-

ronal atrophy in mesocorticolimbic structures, may

act as a critical trigger for the initiation and mainte-

nance of alcohol dependence  [80,  83].

Accordingly, it is commonly recognized that

BDNF not only acts as a central regulator of the

formation of dependence and its clinical manifesta-

tions in the CNS, but also regulates metabolic pro-

cesses outside the brain, although its involvement in

the development of somatic complications of chronic

alcohol consumption is poorly studied. According to

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meta-analyses, individuals with diabetes and meta-

bolic conditions associated with impaired glucose tol-

erance, insulin resistance, and metabolic syndrome,

have reduced peripheral BDNF levels  [57,  58]. In ad-

dition to neuroendocrine mechanisms involved in eat-

ing behavior, BDNF dysregulation contributes to the

diabetogenic potential of chronic alcohol consump-

tion  [84]. Nevertheless, the molecular and cellular

mechanisms through which BDNF influences systemic

metabolic disturbances in alcohol dependence remain

largely unexplored, and dedicated reviews on this

topic are scarce, with the notable exception of the

article by Kim and Kim  [84]. The aim of this review

section was to identify, analyze, and summarize ex-

perimental and clinical evidence regarding the role of

BDNF as a potential link between central and periph-

eral processes in alcohol dependence and associated

somatic complications.

Experimental studies. In rodent models, BDNF

deficiency has been associated with the development

of diabetes, hepatic dysfunction, and behavioral ab-

normalities, particularly under alcohol exposure com-

bined with metabolic disturbances in Otsuka  Long–

Evans Tokushima Fatty (OLETF) rats, a well-estab-

lished model of type  2 diabetes, alcohol intake via a

Lieber–DeCarli liquid diet for 6  weeks significantly in-

creased blood glucose levels in the glucose tolerance

test compared to animals that did not consume eth-

anol  [85]. Ethanol-exposed OLETF rats exhibiting the

highest glucose levels, also showed reduced peripher-

al BDNF levels compared to Long–Evans Tokushima

Otsuka (LETO) rats that did not consume alcohol and

exhibited no signs of diabetes. These findings suggest

that alcohol consumption exacerbates diabetic pheno-

types in parallel with reduction in BDNF.

A high-fat diet (HFD) is a major risk factor for

developing metabolic disorder, including diabetes, in-

sulin resistance, obesity, and liver and brain patholo-

gies. A combination of alcohol consumption and HFD

appears to produce mutual synergistic detrimental ef-

fects. Singh et  al.  [86] investigated the effects of com-

bined HFD and free-choice alcohol consumption on

various types of behavior, neuroinflammation marker,

oxidative stress, and liver function in mice exposed

to these conditions for 12  weeks. The mice exhibit-

ed increased alcohol intake over time, accompanied

by elevated serum corticosterone, aminotransferases,

γ-glutamyltransferase, triglycerides, and lipoproteins,

as well as markers of oxidative stress and pro-inflam-

matory cytokines in both the liver and hippocampus.

The animals also showed cognitive deficits and anx-

iety- and depressive-like behaviors. Importantly, the

identified behavioral and biochemical alterations

were accompanied by a decrease in BDNF expression

in the hippocampus. Intraperitoneal administration

of the BDNF mimetic 7,8-dihydroxyflavone (TrkB ag-

onist) in rats alleviated the effects of combined HFD

and alcohol consumption as the sole source of fluid

for 12  weeks, including memory impairment in the

Morris water maze test, oxidative stress, and inflam-

mation, as well as prevented the decline in BDNF ex-

pression in the hippocampus  [87].

Aerobic physical exercise is widely considered as

a strategy to mitigate metabolic disorders and pre-

vent associated pathologies, including diabetes and

liver diseases  [88]. Its beneficial effects are mediat-

ed through coordinated communication between the

brain, skeletal muscle, and liver through the stimu-

lation of oxidative phosphorylation, fatty acid oxida-

tion, and glucose metabolism. Exercise also increases

secretion of BDNF, which in this context functions as

a myokine promoting muscle regeneration and fat-

ty acid oxidation, while simultaneously acting as a

neuroprotective “molecular hub” that stimulates met-

abolic processes. In mice, chronic ethanol exposure

impaired spatial learning and memory in the Mor-

ris water maze test, with deficits persisting for up to

two months after withdrawal  [89]. Forced treadmill

exercise for 8 weeks prevented these cognitive impair-

ments and was associated with increased hippocam-

pal BDNF expression. However, in another study, vol-

untary wheel running reduced alcohol intake but did

not significantly alter hippocampal BDNF levels  [90].

Notably, β-hydroxybutyrate, a ketone body pro-

duced during prolonged physical exercise, can di-

rectly stimulate BDNF transcription from exon  I

promoter  [91]. The ketogenic diet is another non-phar-

macological approach for correcting metabolic disor-

ders associated with chronic alcohol intoxication  [92].

The increase in BDNF levels observed during ketosis

may contribute to therapeutic effects in conditions

linked to excessive alcohol consumption; howev-

er, this hypothesis remains insufficiently explored

and requires further investigation.

Intraperitoneal ethanol administration, which

models chronic excessive alcohol intake, induces oxi-

dative stress in skeletal muscle in rats and alters the

serum myokine profile, including reduction in BDNF

levels  [93]. These changes have been interpreted as

markers of combined muscle damage, insulin resis-

tance, and impaired cognitive functions. Importantly,

dietary supplementation with selenium, an essential

component of antioxidant enzyme systems, prevent-

ed ethanol-induced oxidative stress and restored the

myokine profile, including normalization of BDNF

levels  [94].

Alcohol abuse is also associated with increased

gut permeability and alterations in gut microbiota

composition, leading to penetration of bacterial cell

wall components into systemic circulation and subse-

quent activation of immune cells  [95]. As mentioned

above, microbiota-derived low-molecular-weight

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metabolites can modulate brain BDNF levels, while

dysbiosis is generally associated with reduced BDNF

expression.

Accordingly, probiotics and prebiotics that nor-

malize the microbiota composition have a beneficial

effect on BDNF levels  [96]. Thus, alcohol-induced dis-

ruption of gut permeability and dysbiosis are likely to

contribute to decreased BDNF expression. In support

of this, fecal microbiota transplantation from mice

subjected to intragastric ethanol administration for

four weeks and exhibiting depressive-like behavior

and reduced BDNF mRNA levels in the hippocampus

upon withdrawal, induced similar behavioral and

molecular alterations in recipient animals  [97]. Mice

that consumed alcohol for 3  weeks developed anxi-

ety- and depressive-like behaviors accompanied by a

downregulation of BDNF mRNA in the hippocampus

and prefrontal cortex and changes in the gut micro-

biota composition  [98].

In different experimental models of stress, BDNF

expression varied depending on the nature of stress-

or and brain region studied; however, most studies

reported a reduction in BDNF levels, particularly in

the frontal cortex and hippocampus of rodents  [99].

Environmental stressors can trigger stress responses

and promote alcohol abuse, while chronic alcohol

exposure and withdrawal themselves act as stressors

that activate the HPA axis. In addition to key stress

mediators such as GCs, corticotropin-releasing hor-

mone (CRH), neuroactive steroids, and norepineph-

rine, disruptions in BDNF expression in specific brain

regions has been linked to the emergence of anxi-

ety-like behavior during ethanol withdrawal  [100].

Chronic alcohol consumption followed by withdraw-

al leads to deacetylation of regulatory regions of the

BDNF gene in the amygdala, resulting in chromatin

condensation and gene transcription suppression,

while reduction in BDNF expression is associated

with anxiety-like behaviors and may further promote

alcohol consumption  [101].

Shukla et al.  [102] demonstrated a complex inter-

action between stress, alcohol-induced gastrointestinal

damage, and development of inflammation. Chronic

stress and alcohol consumption exerted a synergis-

tic effect, elevating corticosterone levels, aggravating

liver damage, and disrupting integrity of the intes-

tinal epithelium in mice. Subcutaneous administra-

tion of corticosterone aggravated alcohol-induced gut

permeability, endotoxemia, liver injury, systemic in-

flammation, and neuroinflammation. Simultaneously,

corticosterone potentiated alcohol-induced decrease

in BDNF mRNA levels in the hypothalamus. In a rat

model, exposure to stress increased voluntary alco-

hol intake, accompanied by elevated plasma corticos-

terone and ACTH levels, as well as increased CRH

mRNA expression in the central amygdala, along-

side decreased BDNF mRNA levels  [103]. The precise

mechanisms underlying BDNF involvement in stress

responses within the context of alcohol dependence

remain poorly understood. However, current evi-

dence suggests that alterations in BDNF expression in

stress-sensitive brain regions represent the outcome

of complex interactions among environmental factors,

neuroendocrine signaling, and peripheral organ sys-

tems. These changes contribute to neuroplastic adap-

tations that underlie behavioral phenotypes charac-

teristic of alcohol dependence.

Clinical studies. Several clinical studies have

demonstrated that in alcohol dependence circulating

BDNF levels are associated with and may co-vary

alongside hormones involved in energy homeostasis,

including leptin, ghrelin, and GLP-1. Beyond their

well-established roles in metabolic regulation, these

hormones have also been implicated in the pathophys-

iology of alcohol dependence syndrome  [104]. Alcohol

abstinence during a one-month rehabilitation program

has been shown to significantly improve metabolic

parameters in individuals with alcohol dependence

and impaired glucose tolerance, including normaliza-

tion of blood glucose levels, insulin resistance, and

insulin secretion  [105]. At the same time, individuals

with prediabetes but not overt diabetes demonstrat-

ed a coordinated increase in circulating BDNF and

ghrelin levels, together with decreased leptin levels.

These findings suggest that restoration of energy me-

tabolism and neuroplastic regulation may contribute

to remission. Consistent with this interpretation, el-

evated plasma leptin levels in patients with alcohol

dependence have been found to correlate negatively

with BDNF concentrations and positively with alcohol

craving severity  [106]. More recently, Tyler etal.  [107]

reported that individuals with alcohol dependence

who maintain abstinence, but not those who continue

alcohol intake, exhibit reciprocal alterations in BDNF

and GLP-1 levels, characterized by reduced BDNF and

increased GLP-1 compared with healthy controls  [107].

Collectively, these data suggest coordinated alterations

in BDNF and hormones regulating energy metabolism,

supporting the hypothesis on interaction between cen-

tral neuroplastic mechanisms and peripheral metabol-

ic regulation in the development of alcohol depen-

dence and associated disorders.

The concentration of BDNF in the plasma of pa-

tients with alcohol dependence who have been in

remission for at least a month was lower compared

to healthy individuals, with even greater reduction

observed in the presence of liver and pancreatic dis-

eases  [108]. In another study, somatic comorbidities

in patients with alcohol withdrawal syndrome did not

influence serum levels of mature BDNF or pro-BDNF;

however, after one week of therapy, pro-BDNF levels

decreased only in patients with comorbidities  [109].

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A significant increase in BDNF content has been re-

ported after two months of alcohol abstinence  [110].

During this period, no considerable changes in liver

elasticity (a marker of fibrotic remodeling) associat-

ed with peripheral BDNF levels were observed, and

serum BDNF levels during abstinence negatively cor-

related with γ-glutamyltransferase (a marker of liver

damage) [110-112]. In individuals with alcohol depen-

dence, reduced serum BDNF levels did not appear to

be associated with conventional indicators of liver

function, such as bilirubin levels, prothrombin time,

or cirrhosis severity assessed by the Child–Pugh score;

however, lower BDNF levels in these patients were

accompanied by decreased handgrip strength  [113].

Additional indirect evidence for the association be-

tween BDNF and alcohol-related liver damage comes

from genetic studies showing that the rs925946 poly-

morphism is associated with an increased risk of de-

veloping liver cirrhosis in individuals with alcohol

abuse  [114]. This variant is located in the 3′-untrans-

lated region of the BDNF gene and has also been

linked to obesity, which is an independent risk factor

for liver fibrosis and its progression to cirrhosis.

It is important to note that changes in BDNF

levels and their association with metabolic indicators

are not observed consistently during therapeutic in-

terventions. For example, serum BDNF levels in alco-

hol-dependent patients undergoing detoxification did

not change significantly and were not associated with

lipoprotein profiles or hepatic enzymes, including

γ-glutamyltransferase and aminotransferases  [115].

Nevertheless, lipid metabolism may still be related

to BDNF signaling in alcohol dependence. Thus, pa-

tients with alcohol dependence exhibit reduced levels

of lysophosphatidic acid, which is a biologically ac-

tive glycerophospholipid that functions as a signaling

molecule  [116]. Importantly, the levels of this lipid

mediator correlate with cognitive impairments and

circulating BDNF concentrations.

Gut dysbiosis in alcohol-dependent individuals

is associated with elevated serum levels of intestinal

fatty acid-binding protein (i-FABP) and lipopolysac-

charide (markers of increased gut permeability and

penetration of bacterial components into circulation,

respectively), alongside reduced serum BDNF lev-

els  [117]. Fecal microbiota transplantation from alco-

hol-dependent patients into rats induces a phenotype

resembling alcohol dependence, including anxiety-

and depressive-like behaviors, memory impairment,

increased alcohol preference, and reduced BDNF ex-

pression in the brain. Conversely, restoration of gut

microbiota composition is accompanied by normal-

ization of BDNF levels. For instance, dietary supple-

mentation with the prebiotic inulin in patients with

alcohol dependence altered microbiota composition

and increased serum BDNF levels, although it did

not significantly affect anxiety, depression, or alcohol

craving  [118].

The HPA axis is disrupted at all stages of the

alcohol dependence cycle. Cortisol reactivity is most

pronounced during withdrawal, while in the early

post-abstinence period, conversely, a reduction in

stress responsiveness is observed, reflected by de-

creased ACTH and cortisol levels  [119]. While with

prolonged abstinence, stress sensitivity may gradual-

ly normalize. In the context of alcohol use disorder,

blood BDNF may serve as an indicator of stress re-

activity. Acute psychosocial stress in the Trier social

stress test increased peripheral BDNF alongside ACTH

and cortisol levels in volunteers regardless of the

presence of alcohol dependence, without a significant

correlation between BDNF and these hormones  [120].

In contrast, in alcohol-consuming individuals without

clinical signs of dependence, acute stress induced

a decrease in serum BDNF, with the magnitude of

this response partially influenced by family history

of alcohol dependence and age of first alcohol expo-

sure  [121]. In male patients with alcohol dependence,

serum BDNF levels remained stable during two

weeks of abstinence following withdrawal; however,

in individuals with elevated cortisol, BDNF showed

a negative correlation with testosterone and a pos-

itive correlation with alcohol craving severity  [122].

Furthermore, reduced plasma BDNF and impaired

amygdala–prefrontal cortex connectivity during an-

ticipation of an unpredictable aversive stimulus

(electric shock) have been associated with a great-

er number of alcohol consumption episodes in the

previous 60  days and an earlier onset of alcohol use

disorder  [123]. Although baseline serum BDNF is not

directly associated with alcohol consumption or early

post-traumatic disorder (PTSD) development following

physical injury, reduced BDNF combined with alcohol

use predicts higher PTSD risk at 12-month follow-up,

but not at early stages  [124]. Therefore, clinical ob-

servations suggest a complex and context-dependent

relationship between BDNF and stress responsivity in

alcohol use disorders. This relationship appears to be

influenced by stressor type and duration, endocrine

status, severity and duration of alcohol exposure,

and family burden. Nevertheless, reduced BDNF lev-

els may generally indicate increased vulnerability to

stress-related dysregulation.

Chronic excessive alcohol consumption is also

associated with increased risk of developing cardio-

vascular diseases, including cardiomyopathy, arrhyth-

mia, and ischemic heart disease  [125]. BDNF plays a

regulatory role in cardiovascular physiology by influ-

encing cardiomyocytes, vascular smooth muscle cells,

and endothelial cells  [126] and acts as a mediator of

the heart–brain axis implicated in the comorbidity

of cardiovascular and psychiatric disorders [127].

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Fig.  2. BDNF as a mediator of the central and systemic effects of ethanol in the development of dependence. Chronic alcohol

intoxication is associated with widespread damage to organs and tissues, in which ethanol itself, along with its metabolites

acetaldehyde and acetate, contribute to cellular injury. The key mechanisms of systemic damage include oxidative stress,

inflammatory responses, and disruption of energy homeostasis. BDNF plays a dual role in this context. Due to its involve-

ment in CNS plasticity, it participates in the development and maintenance of alcohol dependence and its manifestations.

Beyond the brain, BDNF is involved in the regulation of peripheral metabolic processes; however, its contribution to so-

matic complications of chronic alcohol consumption remains insufficiently characterized. Current evidence suggests that

BDNF deficiency represents a common convergent pathological factor linking central mechanisms of addiction, increased

vulnerability to stress, and systemic metabolic dysfunction, particularly through interactions with the endocrine system.

Collectively, these factors lead to the development of alcohol-related somatic complications, including dysbiosis, disruption

of intestinal wall permeability, liver and skeletal muscle pathology, insulin resistance and obesity, diabetes, and potentially

cardiovascular diseases. The diagram was prepared using graphic templates from Servier Medical Art (Servier) available

under the Creative Commons Attribution  4.0 Unported License.

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BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026

Overall, reduced BDNF levels are associated with

cardiovascular pathology [128-130]. Although direct

evidence linking BDNF to alcohol-induced cardio-

vascular disease remains limited, existing literature

suggests that cardiovascular complications associated

with alcohol use disorders are likely to involve BDNF

deficiency.

CONCLUSION

Truffaldino: Well, there’s no mistake about me

being the servant of two masters.

They have both paid me my wages.

The Servant of Two Masters by Carlo Goldoni.

Act 2, scene 3.

(Translated by Edward Dent)

Like the protagonist of Carlo Goldoni’s comedy,

the quick-witted Truffaldino from Bergamo, who,

thanks to his (neuro)plasticity, manages to serve two

masters at once and ultimately brings them together,

BDNF is essential both for systemic metabolism and

brain function, playing a central role in linking the

two. During the states of active metabolism, such as

physical activity or hunger, BDNF mediates bottom-up

signaling, in which peripheral cues trigger the release

of molecules that reach the brain and activate the

BDNF gene. At the same time, BDNF exerts the top-

down control by sending signals that influence sys-

temic metabolism (Fig.  2). In this way, it functions as

a dynamic bridge between peripheral metabolism and

higher-order neural activity. BDNF can thus be under-

stood as a “molecular currency”, translating physical

health into brain’s cognitive reserve and vice versa.

This integrative role helps explain why disruptions

in BDNF signaling may contribute to both peripheral

and central metabolic disorders, including those asso-

ciated with various diseases, particularly the develop-

ment of alcohol dependence.

Although this review covers the majority of

available studies, it should be emphasized that, de-

spite the practical relevance of the topic, there is a

striking paucity of research elucidating the mecha-

nisms through which BDNF signaling is involved in

alcohol-related pathologies. Existing experimental and

clinical data are largely descriptive and provide only

indirect evidence. Consequently, it remains difficult

to draw definitive conclusions regarding causal rela-

tionships or to clarify the role of BDNF in disruptions

of fundamental metabolic processes in the context of

alcohol-related disorders. Current evidence suggests

that BDNF deficiency may act as a potential trigger

in the development of somatic complications related

to chronic alcohol abuse. It is also evident that effec-

tive treatment of alcohol dependence should take into

account comorbid somatic conditions. In this context,

both pharmacological and non-pharmacological in-

terventions aimed at enhancing BDNF synthesis and

secretion represent promising strategies for correct-

ing dependence-related and metabolic disturbances.

Although existing data indicate that both central and

peripheral BDNF may serve as a key link between

systemic metabolism and neuroplastic processes in

the development of alcohol dependence, further re-

search is required. In particular, future studies should

focus on the BDNF interaction with other neuroendo-

crine regulators, including insulin, insulin-like growth

factors, leptin, ghrelin, and GLP-1.

Abbreviations

BDNF brain-derived neurotrophic factor

GC glucocorticoid

GLP-1 glucagon-like peptide-1

HPA axis hypothalamic-pituitary-adrenal axis

p75NTR low-affinity neurotrophin receptor

TrkB tropomyosin-related kinase  B (high-af-

finity BDNF receptor)

Contributions

Both authors developed the review concept, per-

formed literature search and data analysis, and edit-

ed the manuscript; D.I.P. wrote the section on BDNF

role in the pathogenesis of alcohol dependence;

N.V.G. wrote Introduction, Conclusion, and sections on

BDNF involvement in coordination of metabolism and

brain function.

Funding

The work was carried out within the state assignment.

Ethics approval and consent to participate

This work does not contain any studies involving hu-

man or animal subjects.

Conflict of interest

The authors of this work declare that they have no

conflicts of interest.

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