*2.1.2. Macrophages*

have singular cellular composition, anatomical location and pathophysiological properties

In lean individuals, macrophages count for around 5% of WAT's cells depots, in obesity conditions, macrophages increase as much as 50% [1]; nevertheless, besides quantitative changes, there also occurs qualitative ones. The main function of macrophages (or initially described) have been phagocytosis, however, nowadays, they are recognized as a heteroge-

Three types of adipocytes have been described: white, beige (brite, brownish) and brown adipocytes; these are different in structure and metabolism [26]. The terms white and brown came from the appearance of tissues when stained with immunohistochemistry against

a unilocular large lipid droplet and comprise predominantly the WAT [8, 26]. Many functions are attributed for these cells such as insulation and physical protection of the viscera, thermal insulation, reservoir of stored energy in form of triglycerides and regulation of fat release and storage. Beyond these functions, white adipocytes produce and secrete several molecules (adipokines), including leptin, resistin, retinol binding protein 4 (RBP4), fibroblast grown factor 21 (FGF21) and adiponectin mainly. Endocrine communication of adipose tissue is bidirectional, white adipocytes also respond to hormonal signals to induce lipolysis and release free fatty acids (FFAs) into the circulation, for oxidation or storage by other tissues [8, 26].

Brown adipocytes are multilocular with small lipid droplets and express uncoupling protein-1 (UCP-1) [26], emerge from Myf5+ precursor lineage and are developmentally more related to skeletal muscle cells than to white adipocytes. The amount and location of brown adipocytes changes throughout life, in the early years, the number of reservoirs is higher and is mainly located in breastbone, interscapular space and retroperitoneal level; whereas in adults, it decreases and can only find deposits in carotid bodies, aortic bodies and adrenal gland. The main function of these adipocytes is thermogenesis, keeping temperature homeostasis in cold. This is because brown adipocytes possess a large number of mitochondria, and these in turn, express UCP-1 in the inner membrane. This protein decouples the electron transport chain, making it more inefficient, thus the number of ATPs produced decreases and energy is

The name brite is the result of combining brown (br) and white (ite), since this kind of adipocytes was described to be morphologically similar to white adipocytes but at the same time, they expressed minimum levels of UCP-1 [26]. The discovery of this kind of cells challenged the initial idea of WAT and BAT as two different tissues [31, 32], and opened the possibility of considering them as a single adipose organ [33]. Beige adipocytes arise in subcutaneous white adipose tissue from precursors expressing CD137 and transmembrane protein 26, under the condition of low temperatures or β-adrenergic-receptor stimulation. When the stimulus stops, the cells appear to return to white cells, however, upon re-stimulation

preadipocyte lineage, which have

neous population with multiple functions [1, 2].

160 Adiposity - Omics and Molecular Understanding

White adipocytes are specialized cells, arising from a Myf5−

[25].

*2.1.1. Adipocytes*

UCP-1 [27, 28].

dissipated as heat [29, 30].

Macrophages were reported by Elie Metchnikoff in 1884. For many decades, they were considered to be a homogeneous lineage with a main function, phagocytosis. Now they are recognized as very plastic immune cells with multiple functions, because of this, their population is highly heterogeneous and difficult to classify, but two main phenotypes (subtypes) are generally accepted: classically (M1) or alternatively (M2) activated [37, 38].

The M1 phenotype is promoted by T-helper 1 (Th1) cytokines (i.e. interferon (IFN)-γ) or by pathogen-associated molecular patterns (PAMPs) (i.e. LPS) and is characterized by the production of pro-inflammatory cytokines (IL-6, TNF-α, IFN-γ, IL-1β, IL-12 and IL-23), chemokines promoting inflammatory infiltrate (CXCL9,10,11,13, CCL8, 15, 19, 20), and expressed on surface high levels of MHCII, CD80, CD86 and CD11c, among other markers (i.e. Ly6C, CD11b, CD62L, CCR2, CX3CR1 and CCR5). In nucleus, STAT1 and IRF5 are the consensus transcription factors [37, 38].

In contrast, T-helper 2 (Th2) cytokines (i.e. IL-4, IL-10 and IL-13) drive the M2 phenotype, with high phagocytic capacity, and secrete extracellular matrix components, angiogenic and chemotactic factors (CCL17, 18, 22, 24), anti-inflammatory cytokines (IL-10) and the transforming growth factor β (TGF-β), then M2 activates expression of immunosuppressive factors and the peroxisome proliferator-activated receptor gamma (PPARγ) that promotes tissue remodelling and helps to resolve inflammation [37, 38].

Generally, in lean individuals, M2 exists in the WAT; however, the accumulation of adipose tissue leads to increased number of macrophages, besides, the macrophages display M1 phenotype. There are two possible explanations for this phenomenon: (1) environmental factors present in adipose tissue of obese individuals causes a switch in phenotype from M2 to M1; (2) on the other hand, the increase in chemokines (such as CCL2) promotes the recruitment of circulating monocytes and due to the low-grade inflammation state they differentiate to M1 [10, 37].
