Аннотация (русский):
Introduction. Traditionally, mammalian adipose tissue is divided into white (white adipose tissue – WAT) and brown (brown adipose tissue – BAT). While the functions of WAT are well known as the triglyceride depot, the role of BAT in mammalian physiology has been under close investigation. The first description of the role of BAT in maintaining thermogenesis dates back to 1961. This article offers a review of structural and functional specificity of white, beige and brown adipose tissue. Results and discussion. The differences and descriptions of adipocytes and their impact on the maintenance of the main functions of the mammalian body are described in this manuscript. In particular, thermogenesis, stress response, obesity, type II diabetes. In addition to WAT and BAT, an intermediate form was also detected in the body – beige fat (BeAT or Brite). The opposite opinions regarding the presence of three types of adipose tissue in the human and animal bodies are presented. Studies on the identification of uncoupling proteins 1 and 3 and their role in the transformation of white fat into beige/brown are considered. Basically, the data on the factors of endogenous and exogenous nature on their formation are given on the example of the human body. Conclusion. With an abundance of publications on the keywords: “white, brown fat”, these studies, in the overwhelming majority, are devoted to the role of these fats in the formation of human thermogenesis, the assessment of the impact on obesity. Pigs have also been suggested to lack functional BAT, which is a major cause of neonatal death in the swine industry, therefore the focus on investigating role of different types of adipose tissue in pigs seems very promising in order to understand whether there is a compensating mechanism of thermogenesis.

Ключевые слова:
Fat, beige and brown adipocytes, uncoupling protein, thermogenesis, adipocyte, animal health, livestock

INTRODUCTION
The adipose tissue (AT) tissue is a form of
connective tissue, the cells of which are filled with a fat
drop [1]. AT is distributed throughout the body and plays
the key role in the body energy homeostasis as a lipid
reservoir. Moreover, adipocytes are endocrinologically
active, especially visceral [2, 3]. The content of adipose
tissue and its lipid composition is strongly depended on
biological species, diet, climate, etc.
Historically, adipose tissue of mammals has been
divided into two types, white adipose tissue (WAT)
and brown adipose tissue (BAT) based on its visible
different color, as well as on its different physiological
functions [4]. Anatomically, WAT presented in two
major depots, subcutaneous and visceral around internal
organs and comprises the largest AT volume in most
mammals [2, 4, 5]. WAT is specialized in handling
fatty acids and triglycerides (TGs) and critical for
energy storage, endocrine communication, and insulin
sensitivity [4, 5]. In contrast, amount of BAT is strongly
lower. BAT participates in non-shivering thermogenesis
and largely present in mammals postnatally and
during hibernation [2, 4]. Although BAT is readily
observed in both infant and adult mammals, BAT
is gradually replaced by WAT with aging [2]. Beige
adipose (BeAT) tissue is the third type of AT and
is a result of “browning” of WAT, when brown-like
adipocytes appear at anatomical sites characteristic of
WAT [6]. It is also called Brite (brown-in-white) [7, 8].
Originally, BeAT was observed to arise in response to
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cold exposure; however, such factors, as diet, physical
activity, pre-and probiotics, pharmaceutical and plantbased
substances, etc. can also induce “beigeing” or
“browning” of WAT [9].
Health status, survival of offspring, quality of pig
processing products are strongly depended on proportion
of all three types of AT. This article offers a review of
structural and functional specificity of white, beige
and brown adipose tissue, as well as possibility of its
formation and divergence in pigs.
RESULTS AND DISCUSSION
Characteristics of white, beige and brown adipose
tissue. The general classification of adipose tissue is
based on color of AT, which is corresponded to lipid
content, mitochondrial density and vascularization
(Fig. 1). White adipocytes contain a single lipid droplet
occupying approximately 90% of the cell space [9]. BAT
is highly vascularized, brown adipocytes contain a large
number of mitochondria, but lipid droplet is smaller and
presented in multiple vacuoles [9, 10]. Beige adipocytes
display characteristics of both brown and white fat cells,
the content of mitochondria is higher than in WAT, lipid
droplet is not a single, but bigger than in BAT [9].
Canonically, adipocytes are different in the origin
and thought to arise from the de novo differentiation
of precursor cells, particularly, white adipose stem
cells originate from Myf5 (myogenic regulatory factor)
negative progenitors, whereas brown adipose stem
cells originate from myogenic lineage and express
Myf5 [12, 13]. Othervise, adipose precursors are
heterogeneous, and the exact precursor population for
adipogenesis may depend on the sex, location, age, or
proadipogenic stimulus [14]. However, more than 95%
of the precursors in brown fat are labeled with Myf5-
Cre [15]. Beige adipocytes appears in WAT during
white to brown transdifferentiation or can arise from
adipogenic precursor cells in WAT through de novo
differentiation. Additionally, preadipocytes in WAT
give rise to mature white adipocytes with the potential
to become brite adipocytes at a later point of time,
White adipose
tissue (WAT)
which confirmed that after repeated stimuli most brite
adipocytes localize to the same patches within the depot
after the first stimuli. Such microenvironment factor, as
density of vascularization, the types of stromal-vascular
cells in the adipocyte’s vicinity, the composition of the
extracellular matrix, and the local innervation could also
influence on this process [12, 16, 17].
Different morphology of adipose tissues types
corresponds to other divergences, which is summarized
in Table 1. White adipose tissue (WAT) mainly
maintains energy homeostasis and stores energy in
the form of TGs, which are broken down into FFA
and glycerol with following catabolism to generate
energy when energy demands [10]. It also offers
mechanical protection for muscles and internal
organs has an important role in conservation of body
temperature [18]. Thus, subcutaneous WAT acts as a
shock absorber, providing padding at various anatomic
sites, whereas omental WAT is one of the visceral AT
depots, surrounding and protecting inner organs from
physical injury [19]. Subcutaneous WAT is more prone
to expansion and represents a physiological buffer for
excess energy intake during times of limited energy
expenditure. When this storage capacity is exceeded,
fat begins to accumulate ectopically in areas outside
the subcutaneous WAT [19, 20]. Some WAT has only
biomechanical function, such as infrapatellar AT,
which preserves even upon extreme starvation [21].
WAT is also known as an endocrine organ, especially
visceral, by producing adipokines, involving in lipid
metabolism or transport, immune system, regulation
of pressure, blood coagulation, glycemic homeostasis,
angiogenesis, etc. [18, 22]. Adipose tissue also expresses
receptors for most of these factors that are implicated
in the regulation of many processes including food
intake, energy expenditure, metabolism homeostasis,
immunity and blood pressure homeostasis. Both visceral
fat and subcutaneous adipose tissue produce unique
profile of adipocytokines, but visceral fat appears to be
more active [23]. Excess of WAT is strongly correlated
with obesity and insulin resistance [24]. Exceeded fat
accumulation in areas outside the subcutaneous WAT,
such as lipid accumulation in ectopic tissues (liver,
skeletal muscle, and heart) as well as in the visceral
depots lead to local inflammation, metabolic disorders
and obesity-driven insulin resistance (IR) in WAT, liver,
and skeletal muscle [25].
Brown adipose tissue (BAT) was identified as
a thermogenic organ in 1961, in 1978 BAT was
shown to be the major site of thermoregulatory nonshivering
thermogenesis [33]. However, beneficial
effects of BAT could be also explained with its
endocrine role through the release of endocrine factors,
especially under conditions of thermogenic activation,
such insulin-like growth factor I, interleukin-6,
or fibroblast growth factor-21, which improve
glucose tolerance and insulin sensitivity mainly
by influencing hepatic and cardiac function [34].
Comparatively large amounts of BAT are present in
Nucleus Lipid droplet Mitochondria
Beige (Brite) adipose
tissue (BeAT)
Brown adipose
tissue (BAT)
Figure 1 Comparison of white adipocytes, beige adipocytes
and brown adipocytes in morphology [11]
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the newborns, and then reduced during aging [35].
There is a the general proposal that brown adipose
tissue is rapidly lost postnatally, the implication being
that this process is normally concluded within the first
(few) years of life, and that humans later in life do not
possess more than vestigical amounts of brown adipose
tissue [36]. BAT contains a lot of mitochondria, free
fatty acids serve as substrates for lipid oxidation and
as potent activators of the mitochondrial uncoupling
protein 1 (UCP1) – the crucial trans-membrane protein
which catalyzes heat production at the mitochondrial
level [37]. UCP1 is the only memberable to translocate
protons through the inner membrane of brown adipocyte
mitochondria, uncouples respiration from ATP synthesis
and therefore provokes energy dissipation in the form
of heat while, also stimulating high levels of fatty acid
oxidation. UCP1 homologs were identified but they
are biochemically and physiologically different from
UCP1 [38]. The biochemical activities and biological
roles of the identified UCP2 and UCP3 are poorly
understood [39]. UCP2 is widely expressed in tissues
and cell types, could have particular importance in
the regulation in lipid metabolism and contribute to
resting metabolic rate, fat oxidation, while UCP3
could transport protons with a rate comparable to
UCP1 [40–42]. Thus, it was shown that UCP3 is
highly abundant in BAT and the sensitivity of the
protein expression to temperature is similar to that
of UCP1 [43]. It was also revealed that UCP3 is
expressed in both skeletal muscle and brown adipose
tissue may act as an inducible thermogenin in vivo,
could indirectly mediate thermogenesis by increasing
fatty acid oxidation and metabolite transport [44].
However, UCP2 and UCP3 are not generally responsible
for adaptive thermogenesis, but nonetheless they may
Table 1 Characteristics of white, beige and brown adipose tissue
White adipose tissue (WAT) Beige (Brite) adipose tissue (BeAT) Brown adipose tissue (BAT) Ref.
Function Storage of energy
and endocrine tissue
Adaptive thermogenesis Heat production
and endocrine tissue
16,
26–29
Mitochondria Low, thin, elongated Present (upon stimulation) Abundant, bigger in size
and contain more cristae
Uncoupling protein Nearly undetectable Present (upon stimulation) Present
Iron content Low Upon stimulation (Abundant) Abundant
Correlation with
insulin resistance
Positive Negative Negative
Vascularization Low High upon stimulation High
Lipid composition High level of TGs, DGs
Decreased fractions
of phosphatidylcholine
(PC) and
phosphatidylethanolamine
(PE), with longer (C > 36)
and more polyunsaturated
species, as well as lower
levels of cardiolipin (CL)
Higher contents of phosphatidylethanolamine (PE) and
phosphatidylcholine (PC) fractions, with longer (C > 36) and more
polyunsaturated species, as well ascardiolipin (CL), lyso-PC (LPC)
Higher abundance of phospholipids such as PEs and PCs
(predominantly composed by polyunsaturated LCFAs,
especially DHA)
Higher in FFAs
30, 31
Thermogenic
mechanisms
– UCP1-independent
(Ca2+cycling, creatine cycling)
UCP1-dependent creatine
cycling
32
be significantly thermogenic when fully activated
by endogenous or exogenous effectors [45]. BAT
has negative correlation with obesity and insulin
resistance, increasing BAT mass could improve glucose
metabolism and metabolic health [46]. Thus, it was
estimated that 50 g of BAT can burn as much as 20%
of daily energy intake; therefore even though the BAT
depots are present in small amounts, the activated
tissue has the potential to substantially contribute to
energy expenditure. In addition to using lipids, BAT
also displays a very high rate of glucose uptake under
cold exposure, glucose uptake increases by 12-folds,
dissipating energy as a function of increased blood
flow [47].
Beige – brown in white or brite (BeAT) – an
intermediate type of fat, which is similar functionally to
brown fat – it has a high thermogenicity and contains a
significant number of mitochondria. Nevertheless, beige
adipocytes may secrete certain factors that affect WAT
function, systemic metabolism or both, has negative
correlation with obesity and insulin resistance and
appears upon the stimulation into WAT [29, 48, 49].
BeAT plays the key role in adaptive thermogenesis,
subcutaneous WAT is particularly prone to
browning [50]. Thermogenic capacity of beige fat cells
dependents on the presence of UCP1 [51].
Localization of beige and brown adipose
tissue. Distribution of BAT and BeAT is different,
localization is various in species; it is most studied
in humans and rodents (Fig. 2). In human infant
BAT is located in interscapular and peri-renal areas,
while in adults smaller BAT depots are located in
the anterior cervical, supraclavicular, axillary, periaortic,
paravertebral and suprarenal regions, while
beige fat signature could be formed in supraclavicular,
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Anterior cervical
Supraclavicular
Suprascapular
Axillary
Infrascapular
Interscapular
Periaortic
Paravertebral
abdominal visceral and subcutaneous fat depots [32,
48, 52–57]. However, distribution of human BAT
could be wider. Visceral BAT includes perivascular
(aorta, common carotid artery, brachiocephalic artery,
paracardiac mediastinal fat, epicardial coronary artery
and cardiac veins, internal mammary and the intercostal
artery and vein), periviscus (heart, trachea and major
bronchi at lung hilum, esophagus, greater omentum,
transverse mesocolon) and around solid organs
(thoracic paravertebral, pancreas, kidney, adrenal, liver,
hilum of spleen). Subcutaneous BAT includes depots
lying between the anterior neck muscles and in the
supraclavicular fossa, under the clavicles, in the axilla,
in the anterior abdominal wall, and in the inguinal
area [58]. Beige fat is could be also detected in cervical,
parasternal, supraclavicular, para- and prevetebral
areas [59].
In mouse BAT is located in anterior cervical,
supraclavicular, axillary, interscapular, infrascapular,
paravertebral and perirenal areas, while BeAT – in
anterior subcutaneous WAT, supraclavicular WAT
and inguinal WAT [32, 54, 56]. The main differences
between human and mouse adipocytes are defined.
Human BAT are dispersed and represented a mix of
white, classical brown, and recruitable brite adipocytes,
while murine the main BAT depots are in well-defined
anatomic sites and homogeneously composed of brown
adipocytes [60].
The ways of “browning” of white adipose tissue.
Beige adipocytes were originally observed to arise in
response to cold; however, studies have since identified
that diet, exercise, pre-and probiotics, pharmaceutical
agents, numerous plant-based bioactives, and even
adipokines, can also induce “beigeing” or “browning”
of WAT [61]. Thus, “beigeing” or “browning” of WAT
could be caused by β-3 adrenergic receptor agonists,
(CL 316243, BRL 26830A), short-chain fatty acids
(acetate), dietary factors and organic compounds
(capsaicin (and related capsinoids), plant-produced
Figure 2 Localization of beige and brown adipose tissue
in human and mouse [32, 52–55]
Anterior subcutaneous
Abdominal visceral
Abdominal
subcutaneous
Perirenal
Inguinal
Interscapular
Perirenal
resveratrol, plant-derived berberine (BBR), fish oil,
decaffeinated green tea extract, cinnamon extract,
ginsenoside Rb1, curcumin, quercetin, ginger extract),
nuclear receptors and ligands (farnesoid X receptor, liver
X receptors), microRNAs (miRNA-32, miRNA-455),
drug agents (Thiazolidinediones, Prostaglandin E2,
Gleevec, Beta-lapachone, Slit 2 derived secretory
product, Artepillin C, Adrenomedullin 2), inflammatory
factors (IL-6, IL-4, IEX-1), hormonal factors
(thyroid hormones, Glucagon-like peptide 1, leptin,
melatonin, natriuretic peptides), genetic factors
(PTEN, Cox2, Foxc2, folliculin, Gq, TGF-β/Smad3),
batokines (FGF21, apelin), exercise, PPAR agonists
(rosiglitazone,WY14643), bone morphogenetic proteins
(BMP7, BMP4), metabolites (lactate, β-hydroxybutyrate,
beta-aminoisobutyric acid (BAIBA), retinoic acid),
bariatric surgery (physical reconstruction of the
gastrointestinal tract) [10, 49].
Nevertheless, the most studied factor is cold
exposure. Thus, exposure to cold sensed by the skin and
central signals result in increased noradrenaline release
via sympathetic neurons and subsequent stimulation of
various subtypes of β-adrenergic receptors (ADRBs,
mainly subtype β3) and downstream cyclic adenosine
monophosphate signaling, leading to the proliferation
of brown adipocytes and activation of lipolysis and/or
of thermogenesis [62–64]. However, cold-induced BAT
from adult human neck area consists of classical brown
adipocytes, as well as activated thermogenic fat in the
supraclavicular region is composed of both classical
brown and beige adipocytes [65].
Nutritional induction is also studied. WAT content
is influenced by n-3 PUFA, polyphenols, vitamin D,
vitamin E, vitamin A, carotenoids, BAT – by PUFA,
especially n-3 PUFA, bile acids, BeAT – by amino acid
restriction, capsaicin, bile acids, n-3 PUFA, retinoic
acid [27]. Low protein diet results in activation
of brown adipose tissue, as well as sucrose intake
increase BAT activity. Some of the diet-derived
small molecules shown to increase BAT activity
and browning of WAT, such as acetic, butyric and
succinic acids, ketone bodies. Consumption of chilli
peppers (capsaicin, non-pungent capsinoids), olive
oil (oleic acid), green tea (catechins), raspberry
(RB-ketone), grapes (resveratrol), fish (PUFAs)
also stimulate BAT activation and browning [66].
Cannon and Nedergaard described the mechanism
of transformation controlled by hypothalamus [67].
In the experiment on obese ob/ob mice consumed
cafeteria diet (overfed) an activation of brown fat was
observed – diet-induced thermogenesis (DIT) [33]. In
general, macronutrient content of meals (carbohydrate,
fat, protein amount and type) and dietary bioactive
compounds (capsaicin and capsinoids; tea, caffeine
and catechins; menthol; conjugated linoleic acid,
casein protein, curcumin, garlic powder, procyanidinrich
extracts from black soybean seed, resveratrol and
extracts from ginger family plants, etc.) could affect
BAT and browning process [68]. Interestingly, that
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gut microbiota could contribute to upregulation of
thermogenesis in the cold environment [69]. Zhang et al.
reported that Caulis spatholobi can activate brown
adipose tissue and modulate the composition of gut
microbiota, which is linked with normalization of
thermogenesis during cooling [70].
Most of the research describe functions and role
of WAT, BAT and BeAT in human body. Not many
scientists deal with adipogenic features of white,
beige and brown adipose tissues in other mammalian,
domestic farm animals in particular.
Adipose tissues types in pigs. Database search
sciencedirect.com showed that according to the
keywords “brown fat, white fat”, the system issues
3475 publications for 2020, the number of publications
has doubled in 10 years. 6557 scientific papers were
published in 2020 for the keywords “brown fat,
browning”. When the keyword “pig” is added to these
keywords, the number of publications is reduced to 356.
The analysis of these publications showed that the main
scientific interest is directed on modification of fatty
acid composition, but not on the study of the fat types
and their distribution, although the directed modification
of fatty acid profile is of considerable interest, taking
into account correlation of the fatty acids amount with
long chain activity of mitochondrial uncoupling protein
1 (UCP1), the activation of the mitochondria of brown
fat and non-shivering thermogenesis.
Uncoupling protein 1 (UCP1), is a unique
mitochondrial membranous protein devoted to adaptive
thermogenesis, a specialized function performed
by brown adipocytes [38]. The restricted interest to
BAT and BeAT in pigs is explained that pigs (Suidae)
have a predominantly tropical distribution and lost
functional UCP1 in a genetic event that eliminated exons
3–5 ~20 million years ago [71–73]. They consequently
have also been suggested to lack functional BAT,
which is a major cause of neonatal death in the swine
industry [71]. Despite these inconsistent findings, some
pig breeds, such as the Tibetan pig found on the Qinghai-
Tibetan plateau and the Min pig living in Northeast
China, are well recognized to be cold resistant, and
WAT browning was induced after cold exposure as well
as UCP3 expression was significantly increased. Coldresistant
pig breeds (eight dominant pig breeds found
across China) have evolved a novel mechanism involving
UCP3 in beige adipocytes as the primary thermogenic
mechanism, challenging the orthodoxy based on studies
of mice that only UCP1 may act as a significant source
of thermogenic heat [71]. Pigs do not have BAT, but
beige adipocytes were found in inguinal subcutaneous
WAT, axillary sWAT and perirenal fat from acute coldstimulated
cold-tolerant pig breeds in China, including
Tibetan pigs and Min pigs (Fig. 3) [74]. Differentiated
beige cells were also observed in subcutaneous fat of
Tibetan pigs [71].
As beige adipocytes were observed at least in cold
stimulated adipose tissues from cold-resistant pigs,
UCP1-independent non-shivering thermoregulation
might be justified with temperature maintenance in pigs
or UCP3-dependent thermogenesis in beige adipocytes
as a key evolutionary response in cold-adapted pig
lineages [71, 74]. The studies in this area are important,
especially concerning neonatal death in the swine
industry and expanding the geography of pig farming.
CONCLUSION
White, brown and beige/brite adipose tissues are
considered mainly from the point of view of human
health, paying special attention to their role in obesity
and type II diabetes. Mechanisms and tools of white
adipose tissue browning are intensively studied, as well
as brown and beige/brite adipose tissues localization
and features in different species. The phenotypic and
genotypic study of various breeds of pigs in different
conditions of housing, taking into account climatic
zones, will reveal the main qualitative characteristics
of fat. The new knowledge about beige adipose tissue
with some similarity to brown, which is characteristic
of the neonatal period and almost disappears in the
adult body and has a thermogenic function, opens up
new opportunities for the formation of qualitatively
new characteristics of pig adipose tissue. Using the
knowledge about the influence of a number of endo- and
exogenous factors on the formation of adipose tissue
(white, beige, brown), it will be possible to control the
molecular mechanisms of adipocyte differentiation in
order to obtain not only high-quality pork fat, but also
meat products, and to expand the geography of pig
breeding.
CONTRIBUTION
The authors were equally involved in writing the
manuscript and are equally responsible for plagiarism.
CONFLICT OF INTEREST
The authors state that there is no conflict of interest.

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