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Adipose tissue is a particularly flexible tissue
capable of reduction, expansion or alteration according to appropriate
stimulations. According to its cellular and endocrine functions, the adipose
tissue is divided into two major types, the white adipose tissue (WAT) and the
brown adipose tissue (BAT). While white fat stores energy, brown fat expends it
The current classification of adipose tissue includes a third category, the
beige adipose tissue, which has been detected in humans when stimulated by cold
stress or ?3-adrenoceptor agonists that mimic cold stress and shows thermogenic
properties similar to BAT 19.
The three types of adipose tissues have different
morphology, distribution, gene expression, and metabolic functions 20.
Being the main function of WAT the storage of energy in the form of TAG, its
dysfunction is deeply implicated in obesity and related metabolic disorders.

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The adipose tissueWAT
includes is composed by adipocytes,
vascular tissue and immune cells, all enclosed in an extracellular matrix
formed by proteins such as collagen. Fully mature adipocytes develop from
preadipocytes after undergoing differentiation 21. In
situations of reduced energy expenditure or increased food intake which are
characterized as positive energy balance, In the
feeding state (positive energy balance), mature
adipocytes experience hyperplasia (increase in number) and hypertrophy (increase
in size) to store excess lipid in the form of TAG with consequent change in their
morphology 22-24. Adipocyte
enlargement occurs in parallel with extracellular matrix adjustment, by the
action of proteases that hydrolyze collagen to allow cell hypertrophy, and with
the formation of new vessels (angiogenesis) 25. Adipocytes
have origin in adipose stem cells located in the vicinity of the adipose
microvasculature 26 that, early
in postnatal life or even prenatally, differentiate into preadipocytes and
adipocytes by adipose vasculature stimuli 26. Adipose
tissue is an important endocrine and paracrine organ that communicates with
many other organs in the body by secreting signaling proteins collectively
known as adipokines 17. In addition,
adipose tissue constitutes an important source of circulating exosomal micro
RNAs (miRNAs), which can regulate gene expression in distant tissues and
thereby serve as a form of adipokine 27. Overall,
adipose tissue contributes to the maintenance of energy, lipid and glucose
homeostasis, mediating multiple biological processes such as inflammation,
immunity and metabolism 14,16,28.

Population studies have shown an association between abdominal obesity
and IR. However, the specific molecular mechanisms that lead obesity to related
metabolic pathologies remain unclear. Several hypotheses have been proposed to
explain the development of adipose tissue dysfunction and obesity. The adipose
tissue expandability hypothesis has been corroborated by both clinical and
experimental data and is based on the limitation of the adipose tissue to
expand above a given threshold for a specific individual 29. When an
individual increases in fat mass, the adipose tissue expands until a certain
point where it reaches its limit of storage and is no longer able to accumulate
more fat. At this point, ectopic accumulation of bloodstream lipids in
non-adipose tissues, such as liver, skeletal muscle
and pancreas occurs. Contrary to adipocytes, these tissues are poorly
adjustable to store lipids triggering a lipid-induced toxicity that culminates
in failure of cellular function and results in inflammation and IR 18. 30,31. The
maximal capacity of the adipose tissue is dependent on the type of lipid fat
depots 16, subcutaneous
or visceral, the first being more adipogenic and with greater expansion
capacity (hyperplasia) and the latter metabolically more active, expanding
mainly by hypertrophy with huge infiltration of macrophages and regulated by a large
number of glucocorticoid receptors and a lower number of insulin receptors. It
is well accepted that in humans, peripheral subcutaneous adiposity is not
harmful and may even be protective, acting as lipid-buffering tissue that helps
in the maintenance of the daily lipid fluxes homeostasis, whereas increased
visceral fat is associated with metabolic complications due to its proximity to
the liver through the portal vein together with its diminished expansion
capability 14,29. Therefore,
the risk of MetS progression is closely associated with visceral obesity 32. Moreover,
evidences that the individual adipose expandability threshold is determined by
genetic and environmental factors, may explain why both apparently lean and
obese people are prone to develop IR 33.

Another recognized mechanism linking obesity to IR is the adipose tissue
inflammation mediated by overproduction of pro-inflammatory and anti-adipogenic
cytokines 34. Hypertrophic
adipocytes secrete high levels of pro-inflammatory adipokines, such as leptin,
and FFA that induce macrophage infiltration in the adipose tissue and their activation.
In turn, activated macrophages secrete anti-adipogenic cytokines (Tumor
Necrosis Factor-? (TNF-?), Interleukin -6 (IL-6) and Interleukin-1? (IL-1?)) that
inhibit insulin action 35. Insulin
resistant adipocytes continue releasing FFA, activating macrophages to destroy
compromised adipocytes that in turn secrete even more anti-adipogenic
cytokines, consequently increasing IR in mature adipocytes and blocking preadipocytes
maturation 29.

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