Introduction
Adipose tissue is an organ that performs a lot of significant physiological
functions, which is why excess of adipose tissue in the body results in pathological
states in many of its organs and systems [1].
Adipose tissue is not only a tissue, which stores fat and plays a protective role,
it is also an important endocrine organ where signals sent from different tissues
are generated and integrated. Adipose tissue is both morphologically and
physiologically differentiated [2].
Adipose tissue consists of three types of adipocytes: white, brown, and beige, which
have markedly different functions [3]. White
adipose tissue (WAT) is the body’s main energy reservoir, providing
substrates for other tissues, such as muscle and liver [2]. Brown adipose tissue (BAT), on the other
hand, specializes in heat generation by mechanisms associated with the oxidation of
fatty acids, mainly through specific mitochondrial decoupling protein (UCP1), which
dissipates the proton gradient along the inner mitochondrial membrane [1].
The beige adipocytes (also called inducible brown adipocytes, brown-in-white, or
brite adipocytes) appear to differ from brown adipocytes not only in their
respective location in WAT versus BAT depots, but also in their developmental
program, and their responsiveness to adrenergic signaling with respect to
mitochondrial regulation and UCP1 expression [3]
[4].
Associated with this, we highlight the compartmentalization of adipose tissue in
subcutaneous and visceral [5]. Subcutaneous
fat is located beneath the skin and typically represents 80% or more of
total fat mass in humans, concentrated in the abdominal and gluteofemoral depots
[4]
[5]. In visceral adipose tissue, fat is located in the peritoneal cavity,
corresponding to the omental and mesenteric depots [3]. WAT is an essential endocrine organ, secreting numerous hormones and
other factors, collectively termed adipokines. Adipokines play major roles in
regulating whole-body metabolism, including promoting insulin sensitivity
(e. g., adiponectin), insulin resistance (e. g., resistin, RBP4,
lipocalin), and inflammation (e. g., TNF-a, IL-6, IL-1b, IL-8, IL-18, and
sFRP5) [6].
An important aspect is the fact that the physiological expansion of subcutaneous
adipose tissue, in particular, constitutes a safe storage place for excess lipids,
a
factor that contributes to the protection of the individual against lipotoxicity,
with reduction of ectopic fat accumulation, mainly in the liver and skeletal muscle
[7]. However, when the capacity of
expansion of this tissue is exceeded, dysfunction occurs and does not expand
properly to store the energy excess. This induces ectopic fat deposition in other
tissues that regulates glucose homeostasis, an event commonly defined as
“lipotoxicity”. This mechanism leads to systemic insulin resistance
and an increased risk of type 2 diabetes [8]
[9]
[10]. Numerous deleterious effects have been
associated with the unhealthy expansion of the WAT, including inflammation,
fibrosis, hypoxia, altered adipokines secretion, and mitochondrial dysfunction [4]
[5].
Therefore, the objective of this review is to bring knowledge on mechanisms involved
in the structure of adipose tissue, tissue expandability, adipocyte dysfunction, as
well as the impact of these events on the manifestation of important metabolic
disorders associated with adipose tissue dysfunction.
Literature search
A literature search using Pubmed, Web of Science, Scopus, and Cochrane databases
were used to identify relevant studies, using clinical trials, experimental
studies in animals and humans, case-control studies, case series, letters to the
editor , and review articles published in English, without restrictions on year
of publication. The following keywords, alone or in conjunction, were used to
find relevant articles: “adipose tissue”, “adipose
tissue dysfunction”, “white adipose tissue”,
“brown adipose tissue”, “adipocytes”,
“adipogenesis”, “lipolysis”,
“lipogenesis”, “metabolic dysfunction” and
“obesity”. All eligible studies were in English. For this
review, the inclusion criteria focused on structure and remodeling of adipose
tissue, adipose tissue dysfunction and metabolic implications and main metabolic
disorders arising from adipose tissue dysfunction.
Structure and remodeling of adipose tissue
The adipose tissue is a specialized connective tissue, formed by adipocytes,
surrounded by a basal lamina and reticular fibers and constitutes the largest
reserve of energy of the human body. The excess energy is stored in the form of
triglyclycerides, and its efficiency is due to the ability to be stored in large
quantities, dispensing with the presence of water as a solvent [11]
[12].
The WAT presents large and spherical cells, which are formed by a single drop of
fat that forms after the fusion of numerous smaller droplets and presents septa
of connective tissue containing vessels and nerves [13]. BAT, on the other hand, has its
staining determined by the large amount of mitochondria and blood vessels, as
well as having smaller cells than unilocular ones and presenting a polygonal
shape and numerous droplets of fat in its cytoplasm. This tissue has a reduced
amount in adults, being more present in fetuses and newborns due to its
specialty in heat production, a process stimulated by the action of
norepinephrine [14].
Recent studies have shown that in addition to white and brown adipocytes, there
is also beige adipocyte, which does not present the same embryonic expression
profile in all white fat deposits [1]
[4]
[15]. These differences are important because beige adipocytes may
present different origins and characteristics of other tissues, such as the
amount of nerve fibers, vascularization and environmental exposure conditions.
It is noteworthy that subcutaneous fat presents expressive amounts of beige
cells, occurring mainly by cold stimulation and β3-adrenergic receptors
[16].
Fat cells develop derived from cells called pre-adipocytes, which are associated
with blood vessels and derived from endothelial cells of adipose tissue ([Fig. 1]). During embryonic development,
the vascular network develops before the adipocytes and the extracellular matrix
that supports the blood vessels is the first to be deposited, showing a crucial
role of the vascular system in the development of adipose tissue. Thus, at this
stage of development there is a close communication between stroma-vascular
fraction and adipocytes, which results in a mutual control between angiogenesis
and adipogenesis [17].
Fig. 1 White adipose tissue dysfunction: Hypertrophic expansion
through increased adipocyte size is associated with harmful phenomena
such as increased release of basal fatty acids, release of
pro-inflammatory cytokines, recruitment of immune cells, hypoxia,
fibrosis, decreased adiponectin, and impaired insulin sensitivity.
Pre-adipocytes are multipotent cells, capable of differentiating into
macrophages, muscle or bone progenitors, brown fat, and other cell types.
Pre-adipocytes generate adipokines, paracrine factors, hormones and metabolic
signals differently from mature adipose cells [18]. In addition, they exhibit robust innate immune responses to
bacterial antigens, recruit macrophages and other immune effectors, as well as
participate in the process of regulating the immunological activity of adipose
tissue [19]. Thus, the gene expression
profiles of these cells are closer to those of macrophages than to those of the
fat cells themselves [20].
Pre-adipocytes differ in fat cells in response to insulin-like growth factor 1
(IGF-1), lipids, glucocorticoids, and other signs. IGF-1, for example, is
probably the main promoter of adipogenesis, and not insulin itself, as insulin
receptors are not expressed in high amounts until the pre-adipocytes become
mature adipose cells [17].
There are at least two pre-adipocyte subtypes identified in adipose tissue, the
first with the highest response to replication, differentiation, and expression
of adipogenic transcription factors and lower apoptosis in response to tumor
necrosis factor α (TNF-α). The second is a subtype resistant to
adipogenesis, ensuring that not all pre-adipocytes become adipose cells under
favorable conditions. Such subtypes may facilitate tissue plasticity, for
example by differentiating into fat cells with distinct properties, or by
selecting for the apoptosis-resistant subtype [21]. It is noteworthy that adipocytes have different characteristics
in the various stages of development, and in adulthood, there is a
well-developed vascular network, where each adipocyte is surrounded by at least
one capillary, fenestrated and rich in transendothelial channels, which allow
communication with adipocytes. This vascular network is dynamic and continuously
adapted to the changes in nutritional flows, which influences the behavior of
adipocytes during WAT expansion [22].
About the expansion of subcutaneous adipose tissue, this is determined by the
formation of new adipocytes and by the growth capacity from those already
formed. New adipocytes develop from their precursors, known as pre-adipocytes,
vascular stroma, as well as adipose or mesenchymal stem cells. The expansion of
this tissue is regulated by the expression of genes, proteins and metabolites of
different cell types, and depends mainly on the total number of stem cells
available to differentiate into new adipocytes [3]
[23].
Adipocyte hypertrophy is usually associated with abnormal capillary formation,
while hyperplasia is associated with increased angiogenesis and the development
of new capillaries, the latter being the least harmful form of adipose tissue
expansion, given the formation of small, well-irrigated adipocytes with less
inflammatory activity than hypertrophic ones [24].
In order to store excess energy, the adipose tissue undergoes remodeling
processes, among them: (1) Higher nutrient flux [1]; (2) Tissue expansion through coordination of hypertrophy
and/or hyperplasia [2]; (3)
Microvascular compression by the adipocytes' hypertrophy [2]; (4) Reduction of O2
saturation on the cells [5]; (5) Increase
mitochondrial dysfunction and Reactive Oxygen Species (ROS) generation on
mitochondria [1] (6) Impairment on Redox
homeostasis, increasing ROS production [1]; (7) Pro-oxidative environment and with endoplasmic reticulum (ER)
stress [25]; (8) ER stress and
mitochondrial dysfunction [25]; (09)
Oxidative Stress [3]; (10) increase the
macrophage migration and polarization to a pro-inflammatory phenotype, and (11)
Remodeling of the vasculature and extracellular matrix [25].
It is worth mentioning that during the process of expansion of adipose tissue,
local hypoxia phenomena may occur, which increases the expression of angiogenic,
cytokine and adipokine factors. The balance between these factors determines the
density and permeability of the vessel and, therefore, the physiological or
pathophysiological expansion of the adipose tissue [26].
That being the case, angiogenesis is a physiological process through which new
blood vessels form from preexisting vessels, being important for the maintenance
of adequate tissue remodeling and expansion [27]. In WAT remodeling, the angiogenesis frequently precedes
adipogenesis, however, in an inefficiency situation, such process seems to play
an important role in adipose tissue dysfunction [28]
[29].
It is appropriate to mention the important role of the extracellular matrix in
the tissue expansion process of adipose tissue as it deals with a complex
structure composed of different proteins, proteoglycans and polysaccharides and
is involved in the modulation of biological processes such as cell adhesion,
migration, repair, survival and development. In adipose tissue, in particular,
the extracellular matrix is composed mainly of collagen types I, II, III and IV,
fibronectin and laminin, besides allowing the formation of new blood vessels,
essential process in the expansion of healthy adipose tissue [30].
The adipose tissue expansion depends on extracellular matrix remodeling through
hydrolysis/collagen redeposition cycles. However, when its expansion
occurs in a dysfunctional way, excessive and unregulated accumulation of
collagen and other extracellular matrix components occurs, resulting in
fibrosis, which limits the adipocyte expansion capacity [31].
Metabolic and endocrine functions of the adipose tissue
Regarding the metabolic functions of WA, it must be noted that in a situation of
positive energy balance, this tissue has the function of storing energy in the
form of lipids, mainly in intracellular triacylglycerol droplets [32]. These droplets are coated by a group
of proteins, the main one being Perilipin A (PLIN A), which prevents the contact
of the triacylglycerols stored with the cytoplasm [33]
[34].
However, in a negative energy balance situation, lipolysis occurs, a process
characterized by the hydrolysis of triacylglycerols in free fatty acids and
glycerol, which in turn, are released into the bloodstream and later used by
other tissues [35]. In this way, adipose
tissue is able to recognize the metabolic state of the organism, not only by
local energy sensors, but also by means of different signaling pathways, mainly
of the intestine [11]. In addition,
adipose tissue has other functions such as thermal insulation, action in
inflammatory processes, besides playing an important role in glucose homeostasis
and endocrine function, such as leptin release [12].
The main metabolic actions of WAT are classified into lipogenic and lipolytic
activities. Lipogenic activity involves all metabolic processes that result in
biosynthesis, incorporation and storage of triacylglycerols in the
intracytoplasmic fat droplet. While the lipolytic activity concerns the
hydrolysis of the stored TAG and the release of free fatty acids (FFA) and
glycerol [36].
For the lipogenesis process, there is a need for a glycerol 3-phosphate and FFA
source complexed with coenzyme A (CoA), making up acetyl-CoA, derived from
glycolytic pathway and biosynthesis from acetyl-CoA or FFL uptake, respectively.
Once in the cytosol, the FFL binds to fatty acid-binding proteins (FABP),
which transports it to coenzyme A. This process is performed by another integral
membrane protein, acyl-CoA synthase (ACS). At the end of this stage, acyl-CoA is
taken by another protein, the acyl-CoA-binding protein, to the glycerol 3-P
esterification sites, finalizing the synthesis of TAG, which are transferred to
the cytoplasmic fat droplet [14].
About the lipolytic action, this is characterized by the hydrolysis of the stored
triacylglycerol and consequent release of fatty acids and glycerol into the
bloodstream. This process is dependent on the activation of the enzyme lipase
hormone sensitive and stimulated by catecholamines, particularly in fasting
situation, high energy demand, such as physical exercise, or under stress
conditions. Thus, these catecholamines interact with β3-adrenergic
receptors, increasing free fatty acids in the bloodstream [37].
Regarding the endocrine function of adipose tissue, it is emphasized that this
plays a central role in the control of metabolism and interacts with different
organs and systems, through substances and hormones that act stimulating actions
such as Adipogenesis, substrate secretion and metabolization site of steroid
molecules [38].
Another aspect that has been extensively investigated among the actions of
adipose tissue, deals with its role in antimicrobial defense, wound healing and
inflammation [39]. In this sense, we
highlight the immune cells presented in adipose tissue include macrophages,
neutrophils, dendritic cells, eosinophils, natural killer cells (NK) and
innate lymphoid cells, as well as adaptive immunity cells such as B and T cells
(CD4 and CD8 and regulatory cells T (TREG) [40]
[41].
Macrophages are the most widely studied myeloid cells present in adipose tissue,
and currently two phenotypes with distinct functions have been identified:
classically activated macrophages (M1) and alternatively activated macrophages
(M2). The M1 phenotype differs under the influence of pro-inflammatory cytokines
and acts in the beginning and maintenance of inflammation by producing reactive
oxygen and nitrogen species, nitric oxide synthase and pro-inflammatory
cytokines such as TNF-α, interleukin 1β (IL-1β) and
interleukin 6 (IL-6) [42]
[43]
[44]. The M2 phenotype, induced by anti-inflammatory cytokines such as
IL-4, IL-10 and IL-13, act in the resolution of inflammation and tissue
regeneration [45]
[46]
[47].
In this sense, adipose tissue synthesizes and releases several adipokines,
including interleukin-6 (IL-6), transforming growth factor-β
(TGF-β), adipsins, angiotensinogen, plasminogen activator inhibitor-1
(PAI-1), adiponectin, resistin, visfatin, leptin, and vascular endothelial
growth factor (VEGF) [48]. These
substances perform relevant physiological functions, such as the regulation of
immune response, blood pressure control and glycemic homeostasis [49]
[50].
Adipose tissue dysfunction and metabolic implications
Adipose tissue has a safe threshold of expansion for fat storage, without
development of dysfunction. However, in a situation of prolonged positive energy
balance, the limit of expansion of adipocytes of subcutaneous adipose tissue is
reached. From then on, lipids are stored in the visceral compartment and ectopic
form in several organs in the body, mainly in the liver, heart, kidney, pancreas
and muscles [51].
In this perspective, it should be considered that the absolute fat mass is not
the determining factor for the development of metabolic disorders in obese
individuals, but rather the inability of the white adipose tissue to expand and
adequately accommodate the energy surplus, since the hyperplasia process is
limited and hypertrophy does not meet the high energy demand [52]
[53]. One of the mechanisms that explains the association between
adipocyte hypertrophy and the manifestation of metabolic disorders, involves
alterations in the process of angiogenesis, because the vascularization of these
cells does not follow proportionally the increase in their size, which results
in inadequate supply of oxygen and nutrients, favoring tissue dysfunction [24].
The hypoxia in adipose tissue during its initial expansion induces stress
signaling, which in turn facilitates angiogenesis through positive regulation of
a number of genes, including Vascular Endothelial Growth Factor A (VEGF) [54]. However, continuous signaling via
stress resulting from hypoxia reduces VEGF signaling, resulting in impairment of
angiogenesis, which contributes to increased macrophage infiltration and chronic
inflammation [55].
Associated with this, the limited oxygen supply and excessive deposition of
extracellular matrix components, such as collagen and osteopontin, also trigger
adipocyte necrosis and low-grade chronic inflammation, being the latter
characterized predominantly by infiltration of pro-inflammatory macrophages
[56]
[57]. Hypoxia also promotes positive regulation of hypoxia-inducible
factor 1α (HIF-1α), favoring adipose tissue fibrosis. It is
worth mentioning that HIF-1α is overexpressed in the adipose tissue of
obese people and stimulates the attraction and retention of macrophages in
adipocytes. Thus, in addition to contributing to physical restriction to adipose
tissue expansion, excess deposition of the extracellular matrix can contribute
to adipocyte death, tissue inflammation and metabolic dysfunction ([Fig. 1]) [58]
[59].
A study on the subject found a lower amount of fibrosis in the visceral adipose
tissue of diabetic individuals [60].
Similarly, Lackey et al. (2014) [60] found
lower collagen content in the visceral adipose tissue of metabolically unhealthy
obese patients when compared to metabolically healthy obese patients. Thus,
fibrosis reduction seems to be associated with increased adipocyte hypertrophy,
reduced preadipocyte hyperplasia, evidencing the role of extracellular matrix
remodeling and fibrosis in tissue dysfunction [54].
These events induce macrophage infiltration into obese adipose tissue through
increased expression of both leptin and macrophage migration inhibition factor,
which inhibits tissue macrophage emigration [61]
[62]. In addition, the
supernutrition present in obesity stimulates the secretion of chemokines by
adipocytes, such as the monocyte chemoattractant protein-1 (MCP-1), attracting
monocytes to adipose tissue, which later differentiate into macrophages [63].
The infiltration of macrophages in adipose tissue and the pro-inflammatory
microenvironment installed in obesity leads to the alteration of the phenotype
of these cells to type M1. These, in turn, accumulate around the hypoxic
regions, forming "Crown-like Structures", producing
pro-inflammatory cytokines, such as IL-6 and TNFα, which have a great
impact on the insulin signaling cascade, in addition to contributing to local
and systemic inflammation [38]
[64].
It is important to point out that the polarization of macrophages to type M1 is
also favored by the accumulation of lipids within these cells, since, in an
attempt to reduce lipotoxicity, these cells phagocytize the triglyceride
droplets, which results in the accumulation of lipids within macrophages,
transforming them into foamy cells that, in turn, secrete pro-inflammatory
cytokines, such as IL-6 [65].
The chemokines and cytokines produced in adipose tissue are key regulators not
only in the recruitment of macrophages, but also of other immune cells. With
regard to T-lymphocytes, studies show that the CD8 fraction increases with the
progression of obesity, while the CD4 and TREG fractions decrease. In addition,
CD8 cell infiltration precedes macrophage accumulation in adipose tissue, while
immunological depletion of these cells reduces the infiltration of M1
macrophages and the expression of inflammatory cytokines, indicating that these
cells may be involved in the beginning and maintenance of the inflammatory
cascade in obesity [41]
[66].
It is worth noting that the abnormal polarization of macrophages for type M1
mediates metabolic changes in this tissue, and some studies indicate that the
degree of visceral adiposity and the frequency of infiltrated macrophages in
obese adipose tissue correlate significantly with the progress of
atherosclerosis, insulin resistance and low-grade chronic inflammation [67]
[68].
Neutrophils are also cells that stand out for their recruitment at places of
acute inflammation in obese adipose tissue, being mediated by cytosolic
phospholipase A2α. These cells, in turn, produce elastases, a substance
that can induce insulin resistance by degrading the insulin receptor substrate 1
in adipocytes and hepatocytes [69]
[70]. In addition, neutrophils also secrete
myeloperoxidase, which contributes to systemic inflammation and tyrosine
nitration, leading to a reduction in the levels of this protein and modification
in the function of the insulin β receptor [71]. In this way, the recruitment of these
cells contributes to the development of inflammation and insulin resistance in
obese adipose tissue.
Differently, eosinophils are cells involved in the regulation of adipose tissue
homeostasis, through the production of IL-4, a cytokine essential for the
maintenance of M2 macrophages [39].
Recently, studies have shown that the number of eosinophils is linked to another
population of immune cells called innate lymphoid cells (ILC). These cells, in
turn, are categorized into three subtypes: (i) ILC1, which are activated by
IL-12, IL-15 and IL-18 and secrete IFN-γ and TNF; (ii) ILC2, which are
activated by IL-25 and IL-33 and express IL-4, IL-5 and IL-13, and (iii) ILC3
which are triggered by IL-1β and IL-23 and release IL-17 and IL-22 [72]
[73].
In this context, it was identified that the subtype ILC2 predominates in lean WAT
and contributes to its homeostasis by maintaining the numbers of eosinophils and
macrophages of type M2, since it secretes the cytokines IL-5 and IL-13. In
obesity, the ILC1 subtype produces large amounts of Interferon-gamma
(IFN-γ), thus contributing to the polarization of M1 macrophages and
promoting obesity-related insulin resistance [74].
Similar to the ILC1 subtype, natural killer cells (NK), after activation by
IL-12, IL-15 and IL-18, secrete cytokines and chemokines such as TNF,
IFN-γ, GMCSF and CCL2 and promote the recruitment and activation of
other immune cells at the place of inflammation. In this sense, several studies
have observed an increase in the number of these cells in the adipose tissue and
in the blood circulation of obese individuals or with type 2 diabetes mellitus,
when compared to the control group, highlighting the harmful role of NK cells in
obesity-related inflammation and metabolic dysregulation, as well as
contributing to insulin resistance in obesity ([Fig. 2]) [75]
[76].
Fig. 2 Role of the immune system in lean versus obese adipose
tissue: In lean adipose tissue, CD4-type helper T cells produce
anti-inflammatory cytokines, such as interleukin (IL)-4 and 13, which
promote macrophage polarization to type M2. M2 polarization is also
induced by regulatory T cells (Tregs) and eosinophils via IL-4. M2
macrophages secrete other anti-inflammatory signals, such as IL-10,
which maintain insulin sensitivity in lean adipose tissue. On the other
hand, cytokines secreted by CD8-type T cells, such as IL-6, stimulate
the polarization of M1-type macrophages in obese adipose tissue. Other
immune cells are also higher in obese adipose tissue, which contribute
to insulin resistance, including natural killer cells and ILC1.
Furthermore, in obese adipose tissue, macrophages are not homogeneously
distributed, but aggregated around dead adipocytes, forming crown-like
structures. Foam cells are also present in order to phagocytose lipids
from overloaded adipocytes. M1 macrophages are pro-inflammatory,
secreting cytokines such as TNF-α and IL-1β, which
perpetuates inflammation in obese adipose tissue and causes other
metabolic disorders, such as insulin resistance.
Systemic oxidative stress constitutes another disorder present in the
dysfunctional expansion of adipose tissue, due to an imbalance between reactive
oxygen species production and antioxidant capacity, leading to disruption of
redox signaling and control and/or molecular damage [77]. This disturbance can be classified
according to intensity, ranging from physiological oxidative stress (eustress)
to toxic oxidative load (dysstress), which impairs redox signaling and promotes
damage to biomolecules, with pathophysiological consequences [78]. About this disorder, several studies
have already demonstrated that hypertrophy of adipocytes increases the secretion
of pro-inflammatory cytokines and adipokines, the main contributing factor to
the excessive production of reactive oxygen and nitrogen species nitrogen
species in obese organisms [79]
[80].
The accumulation of reactive species induces DNA damage, including point
mutations and chromosomal aberrations, as well as activates signal translation
pathways, altering the expression of several genes [78]. Chronicity of this process promotes
peroxidation of membrane lipids and aggression to tissue proteins, contributing
to the pathogenesis of several metabolic diseases [81].
When adipocytes reach their expansion limit due to increased fat deposition, it
disrupts metabolic homeostasis causing adipose inflammation and alterations in
autophagy and ER functions (induced ER stress) [82]. Several factors alter ER functions, leading to metabolic
dysfunction within the cell. One of the mechanisms is through, over accretion of
fat in adipocytes, which disrupts normal ER activities, such as protein
folding/maturation and lipid homeostasis. This, in turn, stresses the ER
and activates numerous adaptive responses including unfolded protein responses
(UPRs), ER-associated protein degradation (ERAD) as well as autophagy to
reinstate metabolic homeostasis [77]
[83].
The UPRs are primarily involved in maintaining metabolic stability by governing
proper protein folding or degradation. Yet, continuous activation of UPRs in
adipocytes is detrimental, coinciding with adipose dysfunction leading to
obesity and its related comorbidities [77]
[82]. Uncontrolled ER stress
in adipose tissue indeed could alter cellular functions, including lipid and
glucose metabolism, inflammation, insulin signaling, and autophagy, disturbing
the metabolic equilibrium of adipocytes [83].
In this area, an important aspect that should be highlighted is the effect of
interventions for weight loss, for example bariatric surgery and low-calorie
diets in reducing the number of circulating immune cells in adipose tissue that
implies the attenuation of local and systemic inflammation [84]
[85].
Insulin resistance and dyslipidemia
Regarding the impact of adipose tissue dysfunction on glycemic control and
dyslipidemias, the influence of body fat distribution on changes in glucose
metabolism and dyslipidemias stands out, large visceral fat cells are more
strongly linked to disorders in lipid metabolism, while large subcutaneous
adipose cells correlate with hyperinsulinemia and insulin resistance ([Fig. 3]) [24]
[86].
Fig. 3 Mechanisms of lipid storage in adipocytes and their
mobilization from lipid droplets: Lipolysis is inhibited by insulin
signaling and promoted by other hormones like glucagon, GH, cortisol,
T3, or adrenaline, due to the stimulation of AMPc and HSL. cAMP: Cyclic
adenosine monophosphate; FATP: Fatty acid binding protein; FFA: Free
fatty acids; HSL: Hormone-sensitive lipase; IRS-1: Insulin receptor
substract-1; LPL: Lipoprotein lipase; PerA: Perilipin A; VLDL: Very-low
density lipoprotein.
Regarding the contribution of adipose tissue dysfunction to insulin resistance,
it is worth noting that, in situations where positive energy balance is
associated with dysfunction of subcutaneous adipose tissue, there is an increase
of basal lipolysis in hypertrophic adipocytes, favoring the release of
non-esterified fatty acids (NEFA) into the bloodstream. This process triggers
multiple inflammatory signaling pathways in macrophages and adipocytes, as NEFA
may promote inflammation by binding to Toll-like 2 and 4 receptors through the
Adaptive Protein Fetuin-A (FetA), which results in the activation of Nuclear
Factor Kappa B (NF-κB) [87].
Inflammation favors the manifestation of insulin resistance via activation
mechanisms of NF-κB transcription factor signaling. In this sense,
adipose tissue dysfunction activates the IKK kinase complex, favoring
proteasomal degradation of IκBα, which induces nuclear
translocation of NF-κB, which consequently increases the expression of
target genes of this transcription factor, such as IL-6, TNF-α,
transforming growth factor beta (TGF-β) and receptor for advanced
glycosylation end product, important molecules in the induction of insulin
resistance (RAGE) [88]
[89].
The ectopic fat deposition is also an important factor in reducing local and
systemic insulin sensitivity, and the accumulation of diacylglycerides in
hepatocytes activates protein kinase C (PKC), which reduces insulin-stimulated
phosphorylation of IRS-2 and AKT serine/threonine kinase 2 (AKT2), as
well as the ability to activate glycogen synthesis [90]
[91]. Thus, the ectopic accumulation of fat in the liver results in a
reduction of glucose uptake and increased production of this substrate, which
consequently potentiates insulin resistance [88]
[89].
The ectopic accumulation of diacylglycerols and ceramides in muscle tissue also
activates PKC, favoring the phosphorylation of IRS1 in serine residues impairing
the activation of PI3K, with consequent reduction of glucose transporter
activity (GLUT4) and glucose uptake [88].
Ectopic lipid deposition in the heart results in a form of "cardiac
lipotoxicity" characterized by cardiac insulin resistance, cardiac
myocyte apoptosis and contractile dysfunction, for the reason that
diacylglycerols can also activate various PKC isoforms, involved in the
development of insulin resistance [89].
Regarding dyslipidemia associated with adipose tissue dysfunction, changes in the
performance of important enzymes stand out, such as the increased activity of
hormone-sensitive lipase, as well as the inhibition of lipoprotein lipase, which
contributes to promoting the flow of free fatty acids to hepatocytes, which
increases the synthesis of very-low-density lipoproteins (VLDL-c), and
consequently hypertriglyceridemia [92].
The excess of triglycerides in the bloodstream induces a reduction in the
activity of lecithin cholesterol acyl transferase, an important substrate in the
synthesis of high-density lipoproteins (HDL-c) and phospholipid transport
protein, being the latter responsible for the transfer of triglyceride-rich
lipoprotein phospholipids to HDL-c. This metabolic dysfunction implies the
impairment of the maturation of HDL-c lipoprotein and consequently its role in
the reverse transport of cholesterol [90].
Associated with this, hypertriglyceridemia also accentuates the activity of
cholesterol ester transfer protein, an enzyme that acts on the exchange of
cholesterol esters and triglyceride between lipoproteins and, as a consequence,
with formation of LDL-c and HDL-c particles with low cholesterol concentrations
and rich in triglyceride [93]
[94].
In this regard, it is worth noting that the high serum concentration of LDL-c and
HDL-c particles rich in triglycerides stimulates the activity of the enzyme
hepatic lipase to release apoprotein apoA-I from the HDL-c particle, forming
remnants of HDL-c, these being possibly eliminated by bile, reducing their serum
concentration. Thus, as a result of the reduced HDL-c values associated with the
formation of small and dense LDL-c particles, there is a higher risk for the
development of cardiovascular disease ([Fig.
4]) [95].
Fig. 4 Development of dyslipidemia in obesity; Reference: Jung,
Choi [95]. In dysfunctional
adipose tissue there is an increase in lipolysis and, consequently, a
higher concentration of triglycerides and free fatty acids, which
contribute to a lower activity of lipoprotein lipase. There is then an
increased release of free fatty acids from the adipose tissue to the
liver, which leads to greater production of VLDL-c in this tissue, thus
promoting hypertriglyceridemia. The triglyceride present in the VLDL-c
structure is exchanged for low-density lipoprotein (LDL) cholesterol
esters and high-density lipoprotein (HDL) cholesterol esters for the
esterified cholesterol transport protein, producing triglyceride-rich
LDL and HDL. Triglycerides in these lipoproteins are hydrolyzed by
hepatic lipase, producing small, dense LDL and HDL. Decreased HDL
concentration and the formation of small, dense LDL particles are
associated with an increased risk of cardiovascular disease. EC:
Cholesterol esters; CETP: Esterified cholesterol transport protein; FFA:
Free fatty acids; HDL: High density lipoproteins; HL: Hepatic lipase;
LDL: Low-density lipoproteins; LPL: Lipoprotein lipase; TG:
Triglyceride; VLDL: Very low density lipoprotein. hepatic lipase.
In this scenario, based on the information obtained on the subject, it is
verified that the literature clearly brings the various mechanisms involved in
the dysfunction of adipose tissue, as well as its impact on the development of
important disorders associated with obesity. Associated with this, it is
highlighted that such dysfunction can be achieved in different degrees of
adiposity and is not necessarily related to total adipose mass, which allows its
classification into different phenotypes, such as metabolically healthy and
unhealthy obesity.
