**1. Introduction**

Obesity has been defined by the World Health Organization as the excess of adipose tissue (AT) mass that can be harmful or not for the health. The incidence of this disorder has reached epidemic levels during the last few decades. It is associated with a high risk of developing different pathologies such as type 2 diabetes mellitus (T2DM), cardiovascular diseases, dyslipidaemias

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and cancer, among others. White AT (WAT) dysfunction plays an important role in the development of metabolic disorders associated to obesity. Anatomically, WAT presents a discontinuous distribution in the organism and it is divided into two major depots, visceral and subcutaneous (VAT and SAT, respectively). VAT is mainly located in the abdominal cavity (peri-renal, retroperitoneal (RPAT), mesenteric, omental and gonadal) and SAT is distributed below the dermis (femoral, gluteal, abdominal and gonadal). Studies in humans and animal models indicate that VAT expansion is associated with an increase in metabolic risk and mortality, whereas accumulation of SAT improves insulin sensitivity and reduces the risk of developing T2DM.

WAT increase is the consequence of two processes: the increase in the size (hypertrophy) and/ or in the number of adipocytes (hyperplasia). The form in which WAT expands correlates with the presence or absence of WAT-functional alterations. It is well known that hypertrophy of adipose cells is associated with the change in the pattern of adipokine secretion, increasing the release of leptin [1] and pro-inflammatory cytokines [2], and decreasing the release of adiponectin [2]. This profile of adipokine secretion contributes to the development of insulin resistance (IR) observed in hypertrophic adipocytes [3]. Moreover, the increase in cell size is associated with changes in lipid metabolism [4]. Conversely, adipogenesis activation leads to an increase in the number of adipose cells, and therefore prevents the development of hypertrophy thus contributing to normal WAT function.

WAT has been recently reported to express brown AT (BAT) markers, and its exposure to cold or beta-adrenergic receptors stimulation to increase the presence of brown-like-multilocular cells [5]; this process is called WAT 'browning'. Since these cells are different from brown and white adipocytes, they have been called beige or brite adipocytes (from the combination of brown and white). It is known that brown and beige adipocytes originate from different lineages; while brown adipocytes are generated from MYF5+ precursors, beige ones derive from precursors that express platelet-derived growth factor receptor (PDGFR-α<sup>+</sup> ) and stem cells antigen 1 (Sca1+ ) or from smooth muscle-like precursors that express myosin heavychain 11 (MYH11+ ) [6, 7]. Previous reports have suggested that beige adipocytes could arise through a less-studied mechanism of transdifferentiation of pre-existent white adipocytes. The most important functional difference between beige and white adipocytes is the expression of the mitochondrial-uncoupling protein 1 (UCP-1), which allows the production of heat via the respiratory-uncoupling reaction. UCP-1 is activated by an increase of free fatty acids (FFAs), product of cold-induced lipolysis [8]. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a transcription co-activator which promotes the expression of thermogenic genes during cold-induced browning of WAT. Thereby, enhancing the number of beige adipocytes results quite relevant because of the consequent increase in energy expenditure that would avoid or reduce unhealthy hypertrophic WAT expansion. This could protect organisms against metabolic disorders associated to obesity.

Adipogenesis is a process that can be divided into two sequential steps: (a) commitment of mesenchymal stem cells into adipocyte precursor cells (APCs), acquiring the adipogenic potential and restricting them to the adipocyte lineage; and (b) the terminal adipocyte differentiation wherein APCs under specific adipogenic stimuli differentiate into mature adipocytes. In the first step, APCs begin to express CD34, a cell surface antigen that distinguishes between adipogenic and non-adipogenic cell subpopulations [9]. It is important to highlight that APCs are not a homogeneous cell population, presenting different ability to differentiate into mature adipocytes. This cell ability has been called APCs competency and is mainly determined by the expression of two transcription factors, zinc finger protein 423 (Zfp423) and peroxisome proliferator-activated receptor (PPAR)-γ2, that are considered competency markers. Initially, APCs express Zfp423 [10], which in turn activates the basal expression of PPAR-γ2, a key pro-adipogenic signal that assures APCs conversion into adipocytes [11]. APCs differentiation capacity is inversely correlated with the expression of anti-adipogenic factors, such as preadipocyte factor 1 (Pref-1) and wingless-type MMTV 10b (mouse mammary tumour virus) (Wnt-10b). Pref-1 is produced by APCs and exerts the most potent inhibitory signal of the adipogenic process, by suppressing CCAAT/enhancer-binding proteins (C/ EBPs) gene expression [12]. Pref-1 expression decreases progressively in cells undergoing differentiation, becoming undetectable in mature adipocytes. Also, the increase of Wnt-10b levels inhibits APCs differentiation *in vitro* and *in vivo* [13].

and cancer, among others. White AT (WAT) dysfunction plays an important role in the development of metabolic disorders associated to obesity. Anatomically, WAT presents a discontinuous distribution in the organism and it is divided into two major depots, visceral and subcutaneous (VAT and SAT, respectively). VAT is mainly located in the abdominal cavity (peri-renal, retroperitoneal (RPAT), mesenteric, omental and gonadal) and SAT is distributed below the dermis (femoral, gluteal, abdominal and gonadal). Studies in humans and animal models indicate that VAT expansion is associated with an increase in metabolic risk and mortality, whereas accu-

mulation of SAT improves insulin sensitivity and reduces the risk of developing T2DM.

trophy thus contributing to normal WAT function.

166 Adiposity - Epidemiology and Treatment Modalities

cells antigen 1 (Sca1+

chain 11 (MYH11+

lineages; while brown adipocytes are generated from MYF5+

organisms against metabolic disorders associated to obesity.

WAT increase is the consequence of two processes: the increase in the size (hypertrophy) and/ or in the number of adipocytes (hyperplasia). The form in which WAT expands correlates with the presence or absence of WAT-functional alterations. It is well known that hypertrophy of adipose cells is associated with the change in the pattern of adipokine secretion, increasing the release of leptin [1] and pro-inflammatory cytokines [2], and decreasing the release of adiponectin [2]. This profile of adipokine secretion contributes to the development of insulin resistance (IR) observed in hypertrophic adipocytes [3]. Moreover, the increase in cell size is associated with changes in lipid metabolism [4]. Conversely, adipogenesis activation leads to an increase in the number of adipose cells, and therefore prevents the development of hyper-

WAT has been recently reported to express brown AT (BAT) markers, and its exposure to cold or beta-adrenergic receptors stimulation to increase the presence of brown-like-multilocular cells [5]; this process is called WAT 'browning'. Since these cells are different from brown and white adipocytes, they have been called beige or brite adipocytes (from the combination of brown and white). It is known that brown and beige adipocytes originate from different

through a less-studied mechanism of transdifferentiation of pre-existent white adipocytes. The most important functional difference between beige and white adipocytes is the expression of the mitochondrial-uncoupling protein 1 (UCP-1), which allows the production of heat via the respiratory-uncoupling reaction. UCP-1 is activated by an increase of free fatty acids (FFAs), product of cold-induced lipolysis [8]. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) is a transcription co-activator which promotes the expression of thermogenic genes during cold-induced browning of WAT. Thereby, enhancing the number of beige adipocytes results quite relevant because of the consequent increase in energy expenditure that would avoid or reduce unhealthy hypertrophic WAT expansion. This could protect

Adipogenesis is a process that can be divided into two sequential steps: (a) commitment of mesenchymal stem cells into adipocyte precursor cells (APCs), acquiring the adipogenic potential and restricting them to the adipocyte lineage; and (b) the terminal adipocyte differentiation wherein APCs under specific adipogenic stimuli differentiate into mature adipocytes. In the first step, APCs begin to express CD34, a cell surface antigen that distinguishes between adipogenic and non-adipogenic cell subpopulations [9]. It is important to highlight that APCs are not a homogeneous cell population, presenting different ability to differentiate

) or from smooth muscle-like precursors that express myosin heavy-

) [6, 7]. Previous reports have suggested that beige adipocytes could arise

from precursors that express platelet-derived growth factor receptor (PDGFR-α<sup>+</sup>

precursors, beige ones derive

) and stem

Terminal adipocyte differentiation is under the control of different transcription factors and hormones. PPAR-γ2 is one of the most important factors that induce adipocyte differentiation, and its expression is absolutely required for adipocyte differentiation. C/EBP-α, -β and -δ have been the first transcription factors described as involved in the differentiation of AT cells. The expression of C/EBP-β and -δ increases immediately after induction of adipogenesis and stimulates the expression of C/EBP-α and PPARγ-2. The increase in C/EBP-α occurs at the end of adipogenesis and is more abundant in mature adipocytes, being crucial for the normal sensitivity to insulin in adipocytes.

Several factors influence the biology and adipogenic potential of WAT, which contribute to a healthy or unhealthy expansion that occurs under positive-energy balance. The purpose of this chapter is to discuss the role of three of these factors, such as fructose intake, glucocorticoids (GCs) and testosterone, affecting WAT function and expansion (**Figure 1**).

**Figure 1.** Adipocyte precursor cells (APCs) are committed mesenchymal stem cells that have acquired the adipogenic potential, and are restricted to adipocyte lineage. During healthy adipose tissue (AT) expansion, adipogenesis is active and AT is composed by normal sized and small new generated adipocytes, maintaining normal functions. When AT undergoes an unhealthy expansion, VAT expands mainly by hypertrophy, and becomes dysfunctional, characterized by insulin-resistant adipocytes, with abnormal endocrine function and local pro-inflammatory state.
