ISSN 0006-2979, Biochemistry (Moscow), 2026, Vol. 91, No. 5, pp. 623-636 © The Author(s), 2026. This article is an open access publication.
623
REVIEW
Metabolic Neurophilosophy:
Linking Brain Function with Body Metabolism
Natalia V. Gulyaeva
1,2
1
Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences,
117485 Moscow, Russia
2
Research and Clinical Center for Neuropsychiatry of Moscow Healthcare Department,
115419 Moscow, Russia
e-mail: nata_gul@ihna.ru
Received May 6, 2026
Revised May 6, 2026
Accepted May 8, 2026
Abstract— This special issue of Biochemistry (Moscow) “Interaction between Neural Signals and Metabol-
ic Pathways: Role in the Functioning of a Healthy and Diseased Brain”, includes studies on the mecha-
nisms of close functional connections between the brain and other organs and tissues of the body. These
mechanisms link brain metabolism with its signaling function under normal and pathological conditions.
The metabolic signals that enable these connections are the focus of research in this field, which is crucial
for an integrated understanding of how the body functions. An impairment in metabolic signaling leads to
the development of various pathologies. Metabolites such as glucose, fatty acids, and amino acids act as
primary signals that influence neural networks and brain chemistry. This connection between the body’s
metabolism and brain signaling is not merely a matter of fuel supply, but rather a complex information
exchange process. The interaction between the brain and the body occurs within the framework of coordi-
nated work of two main axes: the brain-to-body axis (“from top to bottom” or from center to periphery),
and the body-to-brain axis (from periphery to center). This relationship between brain function and body
metabolism forms a mechanical and logical connection between metabolic somatic diseases and brain dis-
orders that may underlie their comorbidities. The close connection between brain function, metabolism,
and the metabolism of peripheral organs and tissues forms the basis for treating “body-brain metabolic”
disorders. Identifying the molecular and cellular mechanisms underlying this relationship allows identify-
ing targets for treating and preventing comorbid somatic and brain conditions. The recent achievements,
which prove the close relationship between metabolism and brain activity, have led to the emergence of
a rapidly growing interdisciplinary field at the interface of neuroscience, philosophy of consciousness, and
functional biochemistry of metabolism. This new synthetic field can be called “metabolic neurophilosophy”.
Its subject is to explore the integrity and inseparability of the body’s metabolism (including both in the
brain and peripheral organs and tissues) and the signaling and informational function of the brain. It also
studies the dependence of all brain activity, including cognition, and mental states on energy processes and
metabolic signaling throughout the body.
DOI: 10.1134/S0006297926601450
Keywords: metabolism, brain, stress, energy balance, metabolic disorders, neuroendocrine system, synaptic
plasticity, visceral organs, somatic diseases, brain diseases, mental disorders, neurological diseases, neurode-
generative diseases, comorbidity, neurophilosophy
INTRODUCTION
“It is clear to all that the animal organism is a
highly complex system consisting of an almost infinite
series of parts connected both with one another and,
as a total complex, with the surrounding world, with
which it is in a state of equilibrium. The equilibrium
of this system, as of any other system, is a condition
for its existence. And if in certain cases we are unable
to disclose the purposeful relations in this system,
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the reason is that we lack knowledge; it does not mean
at all that these relations are absent in the system
during its continual existence.” [1]. This quote from
Ivan P. Pavlov’s Nobel Prize speech, which he deliv-
ered in Stockholm on December 12, 1904, reflects
the concept of the body as a complex, self-regulating
homeostatic system that is inextricably linked to the
environment. The special issue of the Biochemistry
(Moscow) “Interaction between Neural Signals and
Metabolic Pathways: Role in the Functioning of a
Healthy and Diseased Brain” is devoted specifically
to the search for “the purposeful relations” at the
molecular level between the most important parts of
the body as a system – the brain/its structures and
peripheral organs/tissues. It is the metabolic signals
that realize these connections, therefore, research in
this field is the core for an integrative understand-
ing of how the body functions and how a violation
of metabolic signaling leads to the development of
illnesses, both somatic and brain diseases.
It is routine to distinguish between two func-
tional groups of enzymes and metabolic pathways.
Core/housekeeping metabolism includes the process-
es necessary for the survival of any living cell, such
as glycolysis, the Krebs cycle, ATP synthesis, DNA
replication, transcription, and protein synthesis by
ribosomes. The second group, known as specialized/
tissue-specific metabolism, includes processes that are
specific to cells of certain tissues. These processes in-
clude the synthesis of neurotransmitters in the ner-
vous system, hormones in the endocrine glands, bile
acids in the liver, insulin in the pancreas, and contrac-
tile metabolism in muscles [2]. This fundamental con-
cept of biology, biochemistry, and molecular biology
has been included in textbooks for a long time and
is supported by data from proteomics and metabolo-
mics [3, 4]. It is estimated that about 44% of all hu-
man genes are expressed in all tissues (housekeeping
genes), while the remaining genes have a more spe-
cialized function. It is the specialization of organs and
their interaction within the body that explains how
and why different tissues use metabolic substrates dif-
ferently. The classical examples from the Lehninger
Principles of Biochemistry [2] are: the gluconeogene-
sis pathway is active in the liver and kidneys, while
respective enzymes are present throughout the whole
organism; the brain uses glucose primarily for energy
production, but the liver also uses it to create glyco-
gen stores and synthesize fats.
It has now become clear that the metabolic spe-
cialization of organs serves as the basis for adaptive
interactions between neural signals and metabolic
pathways throughout the body, and that disruptions
in these interactions underlie the development of
both cerebral and somatic pathologies. To simpli-
fy the consideration of these interactions, we will
separate two main levels: the relationship between
brain metabolism and its specific functions (intrace-
rebral level), as well as the relationship between the
metabolism of peripheral organs and tissues on the
one hand and brain activity on the other. The arbi-
trary nature of this division is evident, since these
levels are interconnected, indeed; however, consider-
ing them separately allows us to identify the specific
patterns of each one.
THE RELATIONSHIP BETWEEN BRAIN
METABOLISM AND BRAIN FUNCTIONS
The metabolism of the brain (and the nervous
system as a whole) differs significantly from that of
peripheral organs and tissues (Fig. 1). First, its en-
ergy metabolism is entirely dependent on glucose
as a substrate [5]. Only under conditions of glucose
deprivation does the brain switch its metabolism to
use ketone bodies as energy substrates [6]. Glucose,
the brain’s primary “fuel,” ensures ATP production,
the regulation of oxidative stress, and the synthesis
of neurotransmitters, neuromodulators, and struc-
tural components. Glucose oxidation in neurons ex-
ceeds that in astrocytes, but in both cases, oxidation
rates increase in direct proportion to excitatory neu-
rotransmission, signal transmission and metabolism
being closely linked at the local level [7].
Second, there is the lactate shuttle, a model of
which was proposed in 1994 by Pierre Magistretti
and Luc Pellerin [8-10]. Neurons specialize in signal
transmission and “delegate” part of their metabolism
to astrocytes, which absorb glucose from the blood,
convert it into lactate, and supply it to neurons that
use lactate as a substrate for their mitochondria.
Astrocytes possess unique anatomical, morphologi-
cal, and metabolic features allowing them to absorb
substrates from the blood and metabolize them for
local delivery to active synapses, thereby support-
ing neuronal function. The mitochondrial respirato-
ry chain is more “compactly” organized in neurons
than in astrocytes, so the bioenergetic efficiency of
mitochondria is higher in neurons. Consequently,
the production of reactive oxygen species by mito-
chondrial complex I is very low in neurons and very
high in astrocytes, and the naturally high content of
reactive oxygen species in astrocytes physiologically
determines a specific transcriptional profile that con-
tributes to the maintenance of cognitive functions.
The energy and redox metabolism of astrocytes must
complement the metabolism of neurons to maintain
normal brain function. This is intercellular metabolic
specialization within the brain: glucose metabolism
is divided between two cell types: astrocytes carry
out glycolysis and “stop halfway,” producing lactate,
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Fig. 1. Brain metabolism and brain signaling function. The diagram illustrates the key components linking brain metabolism
and brain function under normal conditions and in pathological states.
while neurons supply this lactate to the Krebs cycle,
which allows mitochondria to be involved in the oxi-
dation process. Third, there is the glutamate-glutamine
cycle, a specialized process in which neurons release
the neurotransmitter glutamate, and astrocytes take
it up and convert it into glutamine – a metabolite
that is recycled for the synthesis of a new glutamate
molecule (this synthesis is a very energy-demanding
process) [11, 12].
In brain diseases (including neurodegenerative
diseases such as Alzheimer’s disease, Parkinson’s
disease, amyotrophic lateral sclerosis, etc.), critical
metabolic alterations occur in the brain, and as a re-
sult the metabolic specialization and cell cooperation
are impaired. The key change is a decrease in ener-
gy exchange due to glucose hypometabolism. Brain
cells lose their ability to efficiently absorb and break
down glucose, therefore neurons do not have enough
energy to maintain ion pumps and other mechanisms
necessary for conducting nerve impulses, which leads
to impaired signal transmission, neurodegeneration
and neuronal death. Interestingly, hypometabolism
is the earliest sign that is noticeable on positron
emission tomography (PET) scans 10-15 years before
the onset of symptoms of Alzheimer’s disease [13].
Another key factor in the development of brain pa-
thologies is an impairment of the lactate shuttle.
Metabolic disorders are accompanied by reactive
gliosis, astrocytes reduce the metabolic support of
neurons, switching to the synthesis of pro-inflamma-
tory molecules. Without metabolic support, neurons
become extremely vulnerable to any stress factors.
The central event of the hypometabolic state is mi-
tochondrial dysfunction [14, 15]. The processes of
mitochondriogenesis and mitophagy do not proceed
normally, damaged though functioning mitochondria
generate reactive oxygen species, supporting oxida-
tive stress, and electron leakage exacerbates hypome-
tabolism. The glutamate-glutamine cycle is impaired,
as astrocytes are unable to effectively take up excess
glutamate from the synaptic cleft. The hyperglutama-
tergic state of neurons promotes excitotoxicity, and
the constant influx of calcium ions into hyperexcited
neurons triggers programmed cell death [16].
PERIPHERAL TISSUE METABOLISM
AND BRAIN FUNCTION
The main links between peripheral tissue metab-
olism and brain function are shown in the simplest
form in Fig. 2. Metabolism is the “language” in which
the body informs the brain about available resources.
The brain responds by changing its chemical balance
(neurotransmitters) and rebuilding its information
highways (networks). The metabolism of the brain
and the rest of the body are connected through a
system of “request and suggestion”. The brain does
not just consume the resources provided by the body,
but actively controls the metabolism of the periphery
in order to ensure an uninterrupted supply of energy
substrates. Considering these issues, it is routine to
analyze separately the axes connecting the brain to
a specific peripheral organ: brain-liver, brain-heart,
brain-gut, brain-adipose tissue, etc.; occasionally, a
third peripheral organ is added to such an axis [17].
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Fig. 2. The interaction between the body’s metabolism and the functioning of a healthy or diseased brain is carried out
within the framework of the coordinated work of the axes: brain-to-body (from top to bottom, from the center to the
periphery) and body-to-brain (from the periphery to the center). Healthy organism, brain → body. The specific “electrical”
activity of the brain (1)regulates the body’s metabolism through several basic mechanisms. As a result of activation of the
hypothalamic-pituitary link (2) of neuroendocrine regulation, neurohormones trigger several key neuroendocrine axes (3),
including the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-thyroid, hypothalamic-pituitary-gonadal, and
hypothalamic-prolactin axes. Neurohumoral signals regulate metabolic processes, ensuring the activation of adaptation
systems and the maintenance of normal functioning of organs and tissues. By sending electrical and chemical signals to the
peripheral nervous system (autonomic and somatic), the brain additionally regulates the body’s metabolism, in particular
through the sympathetic and parasympathetic parts of the autonomic nervous system (4). Healthy organism, body → brain.
Certain metabolic products of organs and tissues (5) are able to cross the blood-brain barrier and enter the brain (6),
where they can directly interact with neurons and non-neural components. Thus, the brain and the body’s metabolism are
closely related, given that energy for brain activity (mainly in the form of glucose) is supplied to it from the periphery (7).
Sick organism. A violation of the above-described interaction occurs in the diseased organism, and changes in any link
cause either adaptive or pathological changes in other links. For example, when glucose delivery to the brain is impaired
for various reasons (5, 6, 7), the functioning of neurons changes (1), the regulation of the neuroendocrine block (2, 3) and
the peripheral nervous system (4) is disturbed, which leads to metabolic changes in the body and disrupts the regulatory
functions of the body-brain axis, forming a vicious cycle. This scheme, which combines body metabolism and brain function
into a single system, links metabolic somatic diseases (diabetes, obesity, metabolic syndrome, other inherited and acquired
metabolic disorders) with neurological and mental brain diseases (including those accompanied by cognitive decline and/or
affective disorders).
This is due to the fact that the brain is connected
to each peripheral organ by numerous metabolic,
nervous and neurohumoral connections, and consid-
eration of the interrelationships of many organs all
together is possible only at the most general level,
without relevant specific details discussed for simple
peripheral organ-brain axes.
The human brain makes up 2% of the body
weight, but consumes about 20% of the body’s ener-
gy. Nevertheless, it is more energy efficient than most
computers [18]. According to the “Selfish Brain The-
ory” proposed by Achim Peters, when resources are
scarce, the brain prioritizes itself by limiting glucose
supply to the rest of the body through several mech-
anisms [19-21]. The brain, through the sympathet-
ic nervous system, suppresses insulin secretion and
stimulates the release of cortisol; as a result, muscles
and adipose tissue enter a state of temporary “insulin
resistance”, leaving glucose available in the blood for
the needs of neurons. The effects of the brain on the
liver, which are induced, for example, by fasting, are
aimed at increasing blood glucose levels: activation
of glycogenolysis and gluconeogenesis, as well as ke-
togenesis as an opportunity for the brain to use fatty
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acid energy. The brain is considered as a dispatcher
that controls the body’s metabolism in order to con-
stantly receive its 20% of the total energy of the body,
even at the expense of depletion of peripheral organs
and tissues.
The integration of body and brain is realized by
functioning of neurohumoral systems (Fig. 2). The
brain effectively controls the body through the hy-
pothalamic-pituitary-adrenal (HPA) axis and the au-
tonomic nervous system, but in pathological situa-
tions these commands become destructive. HPA axis
is the main interface that translates the “chemical”
language of metabolism into the “electrical/digital”
language of neural signals and vice versa. It pro-
motes conversion of energy resources (glucose, fat)
into behavioral strategies (fight, flight, search for
food). HPA hormones glucocorticoids (GCs, cortisol
in humans, corticosterone in rodents) play the role
of a metabolic manager that effectively redistributes
energy flows between the body and the brain [22].
Realizing the priority of the brain, when HPA axis
is activated, cortisol causes temporary insulin resis-
tance in muscles and adipose tissue. This keeps glu-
cose in the bloodstream, making it available to the
brain. Cortisol stimulates gluconeogenesis in the liv-
er, ensuring the availability of fuel for the high-cost
signaling function of neurons even during starvation.
GCs make a significant contribution to the associa-
tion between metabolism and the specific informa-
tional function of the brain. HPA axis modulates
specific informational processes in the brain through
glucocorticoid and mineralocorticoid receptors in the
hippocampus and prefrontal cortex [23, 24]. Moder-
ate release of GCs enhances long-term potentiation
(LTP) – the cellular mechanism of memory, directing
metabolic energy to memorize information import-
ant for adaptation. Chronic activation of HPA axis in
metabolic disorders (for example, in obesity) causes
dendritic atrophy, negatively affecting cognitive func-
tion [25].
Feedback from peripheral organs and tissues to
the brain is also realized at the HPA level; this key
neurohumoral system not only mediates the “orders
of the brain”, but also perceives body information
through specific sensors. Signaling molecules for
“informing” the brain about the state of energy de-
pots are metabolic hormones, for example, the hor-
mone of adipose tissue leptin and the hormone of
the stomach ghrelin. When hormonal connections are
impaired (for example, in obesity), leptin resistance
develops. The brain interprets a decrease in leptin
signaling as an indication that the body is starving,
although there is an excess of fat, and begins to regu-
late metabolism in the direction of slowing down. The
main mechanism of these phenomena is that leptin
and ghrelin directly modulate hypothalamic activity,
suppressing or enhancing the stress response [26, 27].
Ifthe body signals starvation (high ghrelin), HPA axis
is activated, stimulating the appropriate processes in
the brain. Glucosensing neurons, specialized brain
cells, primarily located in the hypothalamus, arcuate
nucleus and hindbrain, monitor glucose levels and
regulate energy homeostasis by altering their firing
rates. Adrop in blood sugar is a direct signal for HPA
axis to trigger a stress response (release of adrena-
line and GCs) [28]. HPA axis regulates the switching
between brain networks, integrating the body and
brain and converting the metabolic status (hunger/
satiety/inflammation) into a psychophysiological state
(anxiety/tranquility/attention).
Chronic stress transforms HPA axis from a pro-
tective mechanism into a pathological one due to an
allostatic load, making the cost of adaptation too high
for brain [29]. This situation is associated with the
impairment of the normal connections between body
metabolism and brain function. Chronically elevated
GCs significantly impair neuronal energetics. Normal-
ly, GCs provide the energy substrate for the brain,
but under chronic stress, they inhibit glucose trans-
port through the GLUT3 glucose transporter in neu-
rons. As a result, in spite of high blood glucose lev-
els, brain cells cannot absorb and use it, which leads
to energy deficiency and loss of specific functions
(for example, synthesis of complex neurotransmit-
ters) [30]. Normally, astrocytes supply neurons with
lactate, but chronic stress impairs their metabolism.
GCs inhibit the expression of glutamate transporters
in astrocytes, glutamate accumulates in the synaptic
cleft and a hyperglutamatergic state of neurons de-
velops [16, 31]. Chronic activation of HPA axis also
affects the mitochondria, the central link of cellular
energy metabolism. Excessive GCs increase electron
leakage in mitochondria, causing the generation of
free radicals, oxidative stress, and damage to mito-
chondrial membranes and mitochondrial DNA [32].
Cortisol directly suppresses the activity of telomerase,
an enzyme that protects the ends of chromosomes
[33]. Excess GCs also inhibits neurogenesis (especial-
ly in the subgranular neurogenic niche of the hippo-
campus) inducing impairment of brain plasticity [34].
Thus, the connection between the body metab-
olism and the brain signaling systems is not just a
“fuel supply”, but a complex informational exchange.
Metabolites (glucose, fatty acids, amino acids) act
as primary signals that retune neural networks and
brain chemistry. Many neurotransmitters are synthe-
sized directly from precursors that come from food,
so the status of the body metabolism determines their
availability. For example, the level of serotonin in the
brain depends on the transport of tryptophan through
the blood-brain barrier, and insulin facilitates this
transport [35]. The main excitatory (glutamate) and
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inhibitory (GABA) mediators are directly related to
the Krebs cycle. Under metabolic stress (ketosis), the
balance shifts towards GABA, which has an inhibito-
ry and anticonvulsant effect [36]. The dopaminergic
system controls glucose and lipid metabolism through
several mechanisms at the central level (including ap-
petite control and decision-making), regulating body
weight and energy metabolism [37, 38]. In the pitu-
itary gland, dopamine inhibits prolactin production
and stimulates insulin secretion through dopamine
receptor 2. In addition, it can affect various physi-
ological components of the peripheral system, such
as pancreatic beta cells, adipocytes, hepatocytes,
and muscles, regulating secretion of insulin, gluca-
gon and glucagon-like peptide-1, glucose uptake and
utilization, and fatty acid metabolism. An important
link in the metabolic effects of dopamine is the do-
pamine-aminotransferase system [39]. Metabolic dis-
orders (obesity, insulin resistance) are associated with
the decrease in the sensitivity of dopamine recep-
tors [40].
On the other hand, as mentioned above with re-
gard to both leptin and ghrelin, metabolic hormones
also perform the functions of neuromodulators: hor-
mones that regulate metabolism in the body have re-
ceptors in key brain structures (hypothalamus, hippo-
campus, cortex) [41]. So, in the brain, insulin works
not only as a glucose regulator, but also as a signal
of synaptic plasticity. The body’s insulin resistance
“deafens” synapses, preventing them from changing
the strength of the neural connections that underlie
learning [42]. Leptin and ghrelin modulate the dopa-
mine reward system and glutamatergic transmission
in the hippocampus, directly affecting cognitive abil-
ities and decision-making [43]. It is also important
that ATP, the main currency of metabolism, works
in the nervous system as a neurotransmitter through
purinergic receptors. When the body’s metabolism is
impaired, the release of ATP by microglial cells can
trigger a cascade of inflammation, altering the signal-
ing activity of entire brain regions [44].
The default operational definition of neural in-
formation processing is that it is ultimately encoded
as a change in the firing frequency of individual neu-
rons, since this correlates with the presentation of a
peripheral stimulus, motor action, or cognitive task.
It is believed that the metabolic energy that supports
the background activity correlates with differences
in the frequency of neuronal firing. Based on these
concepts, the principles of neuroimaging studies were
developed, in particular, the method of functional
magnetic resonance imaging (fMRI), which are based
on changes in blood oxygen content as an indirect in-
dicator of neural activity. Conceptual frameworks for
fMRI neuroimaging paradigms have been developed
to explore how current neural activity is related to
metabolism [45]. It has been shown that the metabolic
state of the body changes the functional connectivity
of the brain, directly affecting the interaction of neu-
ral networks. With a high level of systemic inflam-
mation (e.g., metabolic syndrome), connectivity in the
“default mode network” (DMN) decreases, leading to
cognitive deficits. Ketosis and intermittent fasting in-
crease the “metabolic flexibility” of neurons, strength-
ening the connection between the prefrontal cortex
and the limbic system [45, 46]. The use of magnetic
resonance imaging in this field of research is very
promising, as it allows for an individual assessment
of both the level of fMRI and the concentration of key
metabolites (choline, N-acetylaspartate, creatine, lac-
tate, lipids, alanine, glutamine and glutamate, GABA,
myo-inositol) using the method of magnetic resonance
spectroscopy. In this special issue, Korotkovet al. [47]
describe a new approach to simultaneous noninva-
sive individual assessment of functional connections
between brain regions and levels of metabolites
in the human brain allowing to track the relation-
ship between these indices in different functional
states.
THE TRANSLATIONAL IMPLICATIONS
OF THE INEXTRICABLE RELATIONSHIP
BETWEEN BRAIN FUNCTION
AND BODY METABOLISM
Energy homeostasis is achieved by the coordinat-
ed action of metabolic organs. The peripheral ner-
vous system innervates the organs and, along with
the neurohumoral system, connects them to the brain
and plays a vital role in the control of energy homeo-
stasis [48]. Maintaining energy/metabolic homeostasis,
providing sufficient energy and essential nutrients, is
implemented by a complex system consisting of re-
dundant pathways that normally guarantee the sta-
bility of this system. Nevertheless, both the function-
ing of the brain-to-body axis and the body-to-brain
axis can be impaired, and such disorders underlie
somatic diseases, brain diseases and their comorbid-
ities. Patterns of interaction between brain regions
involved in cognitive, emotional, and metabolic reg-
ulatory functions may explain why and how many
predisposed people in the modern environment have
impaired mechanisms that determine neural appe-
tite control and energy balance regulation. The brain
controls the internal milieu through hormonal and
neural mechanisms that perceive nutrients. It is con-
stantly influenced by the external environment and
lifestyle, which affect the areas of the brain responsi-
ble for cognitive functions and emotions through sen-
sory input. These two streams of information are in-
tegrated to generate adaptive behavioral (food intake)
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and autonomic/endocrine responses that determine
nutrient distribution, energy expenditure, and overall
energy balance [49]. Any of the peripheral and cen-
tral signaling stages is susceptible to individual pre-
disposition due to genetic, epigenetic, or non-genetic
mechanisms of imprinting at an early age.
On the other hand, impairments of body metab-
olism associated with peripheral organs inevitably
affect the functioning of the brain, since it is the
most “demanding consumer” of energy supplied by
all organs. Any failure in the supply of metabolites
from the outside or other changes in the chemical
composition of the blood immediately affect the neu-
rochemistry of the brain and, consequently, its func-
tion. In the last decade, there has been a growing
interest in understanding how changes in metabolic
functions lead to an increased risk of diseases, in-
cluding diseases of the nervous system [50, 51], and
the number of studies on the complex relationships
between brain function and “metabolic health” is
growing exponentially. Currently, several key univer-
sal signaling mechanisms from the periphery to the
brain are being considered, the failure of these path-
ways potentially resulting in brain pathology.
In metabolic disorders (e.g., obesity or type 2
diabetes), adipose tissue begins to release pro-in-
flammatory cytokines, initiating the development of
systemic inflammation. Even with low-level system-
ic inflammation, cytokines, penetrating through the
blood-brain barrier, activate microglia in the brain,
which leads to neuroinflammation impairing synaptic
plasticity [52, 53]. Metabolic disorders are also associ-
ated with systemic insulin resistance, which is asso-
ciated with insulin resistance in the brain. Insulin in
the brain is involved not only in glucose metabolism,
but is also a signaling molecule involved in memory
and learning mechanisms; insulin resistance impairs
the functioning of the hippocampus responsible for
memory formation [54, 55]. Cognitive functions are
most dramatically impaired in patients with poorer
glycemic control; with increasing duration of diabe-
tes, the rate of cognitive decline accelerates and the
risk of dementia increases significantly [56].
Lipid metabolism disorders affect the state of the
vascular wall and are involved in the development of
microangiopathies and subsequent vascular demen-
tia associated with insufficient supply of glucose and
oxygen to neurons and neurodegeneration [57, 58].
Disorders of the detoxification function of the liver
or kidneys and the accumulation of body metabol-
ic products as a result directly affect brain function
(hepatic and renal encephalopathies) [59, 60]. For ex-
ample, in liver diseases, the level of ammonia in the
blood increases (hyperammonemia), which easily
passes into the brain and is neutralized by astrocytes,
turning into glutamine. Excess glutamine causes as-
trocyte swelling, which is the main cause of brain
edema and subsequent impairment of neuronal func-
tion [61, 62].
Metabolic disorders are frequently accompa-
nied by intestinal dysbiosis. Bacteria produce up to
90% of serotonin and short-chain fatty acids (SCFA),
which are critically important for the integrity of the
blood-brain barrier. As a result, a “leaky gut” is of-
ten associated with a “leaky brain”, allowing toxins,
that normally should have been filtered out, to en-
ter neurons [63, 64]. Currently, impaired functioning
of the gut-brain axis has been documented in almost
all somatic and brain diseases studied in this regard,
including neurodegenerative and psychiatric disor-
ders [65, 66].
At present, there is an obvious trend towards
taking into account metabolic disorders when consid-
ering the pathogenesis of neurological diseases, up to
the consideration of some of them (e.g., Alzheimer’s
disease) as a metabolic disease [67-69]. A number of
researchers approach the substantiation of the “met-
abolic theory of mental health”. Based on the nu-
merous data obtained in the clinic and experiment,
it is proposed to consider mental disorders (includ-
ing schizophrenia, depressive disorders) as metabolic
diseases of the brain [70-73]. Christopher M. Palmer
has summarized abundant evidence that mental ill-
nesses (from depression to schizophrenia) are actu-
ally metabolic disorders of the brain associated with
mitochondrial dysfunction [74]. It is possible to dis-
cuss metabolic disorders in various brain diseases as
a mechanistic basis for their development or as co-
morbid somatic pathologies. The search for metabolic
targets for the treatment of mental disorders is rec-
ognized as an imperative approach to the treatment
of these conditions [75], and the use of appropriate
diets that correct metabolism is considered as one of
the actual possibilities of therapy [76].
Metabolic disorders occupy a special niche in
the development of various forms of epilepsy. More
than 600 different metabolic disorders can lead to a
clinical picture in which seizures are the main neu-
rological manifestation, either as a primary clinical
picture or as part of a more complex phenotype. The
term “metabolic epilepsy” is commonly used to refer
to these metabolic disorders, many of which are as-
sociated with mutations in genes related to metabo-
lism [77]. Symptomatic (structural) epilepsy can cause
metabolic disorders, and those in turn can induce
epilepsy, forming a bidirectional pathological cycle.
Overthe past century, since the very beginning of the
use of ketogenic diets for the treatment of epilepsy, it
has been confirmed that metabolic interventions can
control seizures. For example, metabolic disorders
such as impaired glucose levels and vitamin B6 de-
ficiency can directly cause epilepsy, while epileptic
GULYAEVA630
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seizures themselves can cause lactic acidosis, elec-
trolyte imbalance, and other unfavorable changes of
internal milieu [78]. Impairments of lactate metabo-
lism not only contribute to the pathogenesis of ep-
ilepsy due to acidification of the microenvironment,
but also affect neuroinflammation, imbalance of en-
ergy metabolism, dysregulation of neurotransmitters,
synaptic plasticity and epigenetic regulation through
lactylation, a newly discovered posttranslational mod-
ification that regulates protein functions and gene
expression by covalently attaching lactate groups to
lysine residues [79]. Numerous data highlight the crit-
ical role of neuroinflammation and metabolism inter-
action in the pathophysiology of epilepsy. Metabolic
dysregulation and neuroinflammation exacerbate
each other, creating a vicious circle associated with
pathologically altered metabolism of glucose, gluta-
mate/GABA, tryptophan, kynurenine, adenosine, and
lipids [80, 81]. Metabolic disorders are also associated
with the development of pharmacoresistant epilepsies,
primarily through changes in the metabolic pathways
of alanine, aspartate, and glutamate, as well as the
biosynthetic pathways of phenylalanine, tyrosine, and
tryptophan [82]. These metabolites can be used as
prognostic biomarkers of pharmacoresistant epilepsy
and potential therapeutic targets for the development
of new drugs. It has been shown that astrocytes are
not only involved in the regulation of the metabo-
lism of neural networks, but are also closely associ-
ated with the development of neuroinflammation, a
vital factor associated with the progress of pharma-
coresistant epilepsy [83]. Metabolic reprogramming
of astrocytes and microglia initiates epileptogenesis,
due to the hyperexcitability of neural networks, neu-
roinflammation and oxidative stress. Key mechanisms
of glial dysfunction include a shift to aerobic glycol-
ysis (the Warburg effect), mitochondrial disorders,
and generation of reactive oxygen species [84]. These
processes are regulated by the Wnt/GSK3b and mTOR
signaling pathways and eventually form a vicious
circle of energy deficiency, NLRP3-inflammasome
activation, and excitotoxicity.
Hans Selye regularly stressed the need for a ho-
listic approach when considering the processes oc-
curring in the body: “No matter how much we learn
about the intimate mechanisms of biological phenom-
ena, we shall always have to use the old-fashioned
holistic approach which looks at the living organism
as a complex highly organized system and not as a
mere sum of its parts.” [87]. Remarkably, Selye’s opin-
ion largely coincides with the quotation from Pavlov’s
Nobel Prize speech in 1904 given in the Introduc-
tion [1]. The data obtained in recent decades on the
close metabolic and neural connections between or-
gans as the basis of the body’s existence have made
this “old-fashioned holistic approach” relevant again
and, to a certain extent, it became a trend in funda-
mental medicine, neuroscience and physiology. The
original meaning of the Latin phrase “In a healthy
body, a healthy mind” (Latin: Mens sana in corpore
sano), which dates back to a Juvenal’s satire, was an
appeal to the gods to send down both a healthy body
and a healthy mind. In its modern meaning, this
expression as a slogan of preventive medicine and
the thesis of the relationship between physical and
mental health was consolidated thanks to the philos-
opher and physician John Locke, who, paraphrasing
the ancient source, used this postulate to emphasize
the importance of a healthy lifestyle. The organism
is an integrated metabolic network. It is almost im-
possible to treat brain pathologies in isolation from
the body’s metabolism (and vice versa). To break the
vicious circle, modern medicine increasingly suggests
“treating the brain through the body”: normalize insu-
lin, activate muscles through physical exercises, and
periodically switch the liver to ketone production.
The established intimate relationship of brain func-
tion and metabolism with the metabolism of periph-
eral organs and tissues is the fundamental basis for
the treatment of “from body metabolism to brain”,
while the revealed molecular and cellular mecha-
nisms of this relationship make it possible to identify
targets for the treatment and prevention of comor-
bid somatic and brain diseases. Such targets can be
quite specific or, conversely, universal, such as, for
example, a neurotrophic factor from the brain, BDNF,
a “metabotrophin” that links the signaling function
of neurons and systemic metabolism [85, 86].
CONCLUSION.
NEUROPHILOSOPHY OF METABOLISM
Thus, the metabolic connection between the brain
and the body works both ways. If it was previously
believed that the brain is only a passive consumer of
the body’s energy substrates, modern research shows
that the metabolic connections between the brain and
peripheral organs unite the brain and body so closely
that brain disease “rewires” the metabolism of the
whole organism, and somatic metabolic diseases im-
pairs the functioning of the brain.
Cognitive abilities and behavior are emergent
properties of brain systems that pursue to maximize
complex and adaptive behavior with minimal ener-
gy use, while the human brain’s ability to adaptively
predict, process complex information, and act on it is
associated with a significant energy load [88]. Numer-
ous studies conducted both on models and on large
cohorts of patients confirm the above-mentioned
“Selfish Brain Theory”, which considers the brain as
an independently self-regulating organ that occupies
LINKING BRAIN FUNCTION WITH BODY METABOLISM 631
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026
a primary position in a hierarchically organized ener-
gy metabolism. The theory postulates the vital ability
of the brain to prioritize its own energy metabolism
and is confirmed in clinical studies [89-91]. Basic
brain functions, such as the formation of long-term
memory, increase the metabolic activity of stimulated
neurons to meet energy needs related to brain func-
tion. An evolutionarily (from insects to mammals)
conserved mechanism controls mitochondrial metabo-
lism in neurons, participating in the establishment of
higher brain functions such as memory [92]. The role
of cellular metabolism in learning and memory is
currently beyond doubt. When considering the mo-
lecular mechanisms of learning and memory, it was
suggested that it is the study of neuronal metabolism
that is necessary to understand how the internal
predictive activity of neurons forms a new learning
event [93]. Apparently, the predicted metabolic chang-
es in the brain can also occur in non-neuronal cells,
including peripheral tissues.
The philosophy of consciousness dates back to
antiquity; the subject of this section of philosophy is
primarily the nature of consciousness, as well as the
relationship between consciousness and physical re-
ality (the body). As a biological basis, the philosophy
of consciousness focused mainly on information pro-
cessing (neural and/or network activity). Neurophilos-
ophy, or philosophy of neuroscience, is an interdisci-
plinary study combining neuroscience and philosophy
that examines the relevance of neuroscience research
to issues traditionally related to the philosophy of
mind. With the rapid development of neuroscience,
we are increasingly confronted with neurobiologi-
cal data that address ancient philosophical questions
about consciousness and its relationship to the brain.
The term neurophilosophy was introduced in 1986
by Patricia Churchland as a unified science of the
mind-brain [94, 95]. Neurophilosophy (philosophy of
neuroscience) attempts to interpret neurobiological
approaches and results using the conceptual rigor
and methods of philosophy of science.
Due to achievements of recent years, which show
a close relationship between metabolism and brain
activity, we are witnessing now the birth of a new
synthetic science, which can be called “metabolic
neurophilosophy.” This name reflects the essence of a
rapidly developing interdisciplinary field at the inter-
section of neuroscience, philosophy of consciousness
and biochemistry of metabolism. This field declares
that brain functions, cognition, and mental states
are fundamentally dependent on metabolic processes
and energy availability, and emphasizes the import-
ant role of cognitive and affective functions in the
body’s energy supply, nutrients, and metabolic signal-
ing between peripheral organs and tissues and the
brain. Metabolism is considered not just as a combi-
nation of chemical processes, but as the fundamental
basis of life, the psyche, and even subjective expe-
rience.
Bruce McEwen, a leading researcher on stress,
has shown that the brain, including its higher cogni-
tive centers, is a target of stress and a key organ for
responding to stressors. It is true both in terms of
perceiving what causes stress and in terms of brain’s
ability to determine the effects of stress on both the
brain and the body with the help of neuroendocrine,
autonomic, immune and metabolic systems [29].
These systems, in turn, ensure either successful ad-
aptation or the development of pathologies due to the
combined burden of adaptation to stress and a mal-
adaptive lifestyle– the “allostatic load”. McEwen sug-
gested that plasticity of the brain and its structures
(hippocampus, amygdala, prefrontal cortex) under-
lie learning, memory, and behavior. The features of
changes in neuroplasticity in the process of biological
consolidation of experience throughout life determine
whether events in the social and physical environ-
ment will lead to successful adaptation or to malad-
aptation and mental and physical health disorders.
In particular, it follows from this concept that the
results of brain functioning (including our thoughts)
are metabolic events that shape our physical health.
If the term “metabolic neurophilosophy” is adopted,
the textbook on this discipline will indicate that the
metabolism of the body (including brain and periph-
eral organs/tissues) and the signaling/information
functions of the brain are inseparable. The cognitive
process, emotions, and thoughts are not only “pro-
grams”, but also an energy – consuming physiological
process that shapes the body.
Abbreviations
GCs glucocorticoids
fMRI functional magnetic resonance imaging
HPA hypothalamic-pituitary-adrenal
Contributions
Natalia Gulyaeva developed the concept, carried out
the search and analysis of literature data, wrote and
edited the manuscript.
Funding
The work was supported by the Institute of Higher
Nervous Activity and Neurophysiology, RAS.
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man and animal subjects.
Conflict of interest
The author of this work declares that she has no con-
flicts of interest.
GULYAEVA632
BIOCHEMISTRY (MOSCOW) Vol. 91 No. 5 2026
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