of preadipocytes and adipocytes by adipose vasculature stimuli [26].

ofadipokines Adipose tissue is a particularly flexible tissuecapable of reduction, expansion or alteration according to appropriatestimulations. According to its cellular and endocrine functions, the adiposetissue is divided into two major types, the white adipose tissue (WAT) and thebrown adipose tissue (BAT).

While white fat stores energy, brown fat expends it18.The current classification of adipose tissue includes a third category, thebeige adipose tissue, which has been detected in humans when stimulated by coldstress or ?3-adrenoceptor agonists that mimic cold stress and shows thermogenicproperties similar to BAT 19.The three types of adipose tissues have differentmorphology, distribution, gene expression, and metabolic functions 20.Being the main function of WAT the storage of energy in the form of TAG, itsdysfunction is deeply implicated in obesity and related metabolic disorders. The adipose tissueWATincludes is composed by adipocytes,vascular tissue and immune cells, all enclosed in an extracellular matrixformed by proteins such as collagen.

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Fully mature adipocytes develop frompreadipocytes after undergoing differentiation 21. Insituations of reduced energy expenditure or increased food intake which arecharacterized as positive energy balance, In thefeeding state (positive energy balance), matureadipocytes experience hyperplasia (increase in number) and hypertrophy (increasein size) to store excess lipid in the form of TAG with consequent change in theirmorphology 22-24. Adipocyteenlargement occurs in parallel with extracellular matrix adjustment, by theaction of proteases that hydrolyze collagen to allow cell hypertrophy, and withthe formation of new vessels (angiogenesis) 25. Adipocyteshave origin in adipose stem cells located in the vicinity of the adiposemicrovasculature 26 that, earlyin postnatal life or even prenatally, differentiate into preadipocytes andadipocytes by adipose vasculature stimuli 26. Adiposetissue is an important endocrine and paracrine organ that communicates withmany other organs in the body by secreting signaling proteins collectivelyknown as adipokines 17. In addition,adipose tissue constitutes an important source of circulating exosomal microRNAs (miRNAs), which can regulate gene expression in distant tissues andthereby serve as a form of adipokine 27. Overall,adipose tissue contributes to the maintenance of energy, lipid and glucosehomeostasis, mediating multiple biological processes such as inflammation,immunity and metabolism 14,16,28.

Population studies have shown an association between abdominal obesityand IR. However, the specific molecular mechanisms that lead obesity to relatedmetabolic pathologies remain unclear. Several hypotheses have been proposed toexplain the development of adipose tissue dysfunction and obesity. The adiposetissue expandability hypothesis has been corroborated by both clinical andexperimental data and is based on the limitation of the adipose tissue toexpand above a given threshold for a specific individual 29. When anindividual increases in fat mass, the adipose tissue expands until a certainpoint where it reaches its limit of storage and is no longer able to accumulatemore fat. At this point, ectopic accumulation of bloodstream lipids innon-adipose tissues, such as liver, skeletal muscleand pancreas occurs. Contrary to adipocytes, these tissues are poorlyadjustable to store lipids triggering a lipid-induced toxicity that culminatesin failure of cellular function and results in inflammation and IR 18. 30,31.

Themaximal capacity of the adipose tissue is dependent on the type of lipid fatdepots 16, subcutaneousor visceral, the first being more adipogenic and with greater expansioncapacity (hyperplasia) and the latter metabolically more active, expandingmainly by hypertrophy with huge infiltration of macrophages and regulated by a largenumber of glucocorticoid receptors and a lower number of insulin receptors. Itis well accepted that in humans, peripheral subcutaneous adiposity is notharmful and may even be protective, acting as lipid-buffering tissue that helpsin the maintenance of the daily lipid fluxes homeostasis, whereas increasedvisceral fat is associated with metabolic complications due to its proximity tothe liver through the portal vein together with its diminished expansioncapability 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 bygenetic and environmental factors, may explain why both apparently lean andobese people are prone to develop IR 33. Another recognized mechanism linking obesity to IR is the adipose tissueinflammation mediated by overproduction of pro-inflammatory and anti-adipogeniccytokines 34. Hypertrophicadipocytes 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 (TumorNecrosis Factor-? (TNF-?), Interleukin -6 (IL-6) and Interleukin-1? (IL-1?)) thatinhibit insulin action 35. Insulinresistant adipocytes continue releasing FFA, activating macrophages to destroycompromised adipocytes that in turn secrete even more anti-adipogeniccytokines, consequently increasing IR in mature adipocytes and blocking preadipocytesmaturation 29.