**2. Immunometabolism characteristics on normal weight range and obese individuals**

Immune cell status in normal weight range (lean) individuals is mostly anti-inflammatory; this environment needs a continual production of type 2 cytokines (i.e. interleukin (IL)-5 and IL-13). On the other hand, the presence of obesity is associated with a low-grade inflammation state characterized by increased pro-inflammatory cytokine production (i.e. tumour necrosis factor (TNF)-α, IL-1β and IL-6) (**Table 1**) [10, 24].


M1: macrophages associated with Th-1 cytokines; M2: macrophages associated with Th-2 cytokines; ILC1s: innate lymphoid cells type 1; CCL2: C-C motif ligand 2 and FFA: free fatty acids.

\*During obesity onset, an insulin increase occurs (insulin resistance), after a time it frequently progress to exhaustion of β-cells.

**Table 1.** Changes on immunometabolic components due to obesity.

#### **2.1. Adipose tissue-resident cells**

**1. Introduction**

158 Adiposity - Omics and Molecular Understanding

Inmmunometabolism has been defined as the interphase between metabolism and immune response [1, 2], in which, adipose tissue plays a key role. Leptin was the first molecule described linking the immune system with metabolism. The first leptin function described was appetite control; however, nowadays it has been described with multiple permissive functions, like immune homeostasis, among others (**Figure 1**) [3]. On innate and adaptive immune response cells, leptin can mainly increase cytokine expression, cell surface adhesion molecules and chemokine receptors [3, 4]. Additional to leptin, free fatty acid receptors family (FFARs) has been reported to be expressed on key cell types regulating both: energy homoeostasis and inflammatory responses [2]. Obesity induces changes in gut microbiota, it has been reported that *Bacteroidetes* and *Firmicutes* phyla produce high levels of the short chain free fatty acids (SCFAs) C2–C4 which are the main agonists for FFAR2 [5]; at the same time, microbiota can influence innate and adaptive immune responses [6, 7]. These examples make clear the interrelation between metabolism and the immune system. We will focus along this chapter in

alterations of this interphase due to the presence of obesity.

**Figure 1.** Neuroendocrine immune system.

**and obese individuals**

**2. Immunometabolism characteristics on normal weight range**

Immune cell status in normal weight range (lean) individuals is mostly anti-inflammatory; this environment needs a continual production of type 2 cytokines (i.e. interleukin (IL)-5 and IL-13). Adipose tissue is a specialized connective one, white adipose tissue (WAT) is the most abundant in adult human (∼85%) by its distribution, it can be classified in subcutaneous or visceral (omental, mesenteric and retroperitoneal accumulation). Besides WAT, there exist two more types: brown adipose tissue (BAT) and bone marrow adipose tissue (BMAT), each one have singular cellular composition, anatomical location and pathophysiological properties [25].

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 heterogeneous population with multiple functions [1, 2].

#### *2.1.1. Adipocytes*

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 UCP-1 [27, 28].

White adipocytes are specialized cells, arising from a Myf5− preadipocyte lineage, which have 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 dissipated as heat [29, 30].

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 respond as beige adipocytes [10]. This phenomenon has encouraged the ability to control the differentiation of adipose tissue by increasing energy expenditure to reduce the accumulation of energy in the form of triglycerides, including WAT change to BAT (browning of WAT) under pathological conditions in humans was reported [34, 35]. We should learn more about browning control (on and off) to avoid presentation of undesired effects (i.e. cachexia, atherosclerosis and hepatic steatosis) [27, 36].
