*Flavonoids: A Promising Therapy for Obesity Due to the High-Fat Diet DOI: http://dx.doi.org/10.5772/intechopen.84665*

Different epidemiological studies have shown that the increase in the consumption of diets high in saturated fats and simple carbohydrates leads to the progressive accumulation of intra-abdominal fat mass, accompanied by alterations in their pattern of adipocytokine secretion and in the homeostasis of the metabolism of lipids [9, 10].

There are two main types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT) (**Figure 3**). White adipocytes are the most common fat cells, are present in visceral and subcutaneous adipose tissues, and are responsible for the expansion of fat mass in obesity. On the other hand, brown adipocytes are smaller cells that play a central role in the process of thermogenesis; their deposits are mainly focused on the interscapular and perirenal and around the great vessels, although their deposits are limited according to age advances [10].

In the particular case of obesity and the capacity shown by white adipocytes to adapt their metabolism to the energy demands of the organism, it will depend on the BAT to adequately perform its function as an energy reservoir (uptake of circulating fatty acids, esterification, and deposition as triglycerides (TG)) and prevent ectopic deposits of lipids and, therefore, lipotoxicity in tissues such as the liver and

#### **Figure 2.**

*Mechanisms of inflammation in adipose tissue.* ↓*Decrease,* ↑*increase. Interleukin 10 (IL-10), interleukin 6 (IL-6), tumor necrosis factor alpha (TNFα), Jun kinase (JNK), necrosis factor kappa B (NF-*ᴋ*b), free fatty acids (FFA).*

**Figure 3.** *Types of adipose tissue.*

skeletal muscle. It is important to note that in lipogenesis and TG synthesis in the liver due to a hypercaloric diet, the synthesized fatty acids are incorporated into the triacylglycerides, leading to an increase in the synthesis and secretion of very-lowdensity lipoproteins (VLDL), as shown in **Figure 4**.

When the capacity of the WAT to store TG is exceeded, the activity of lipoprotein lipase of the adipocyte (LPLa) begins to decrease and with it the hydrolysis of TG that is transported by chylomicrons from the small intestine. In the long term, this generates an elevation in plasma levels of triglycerides and c-VLDL. Similarly, the progressive hypertrophy of adipocytes promotes tissue hypoxia, inflammation, and infiltration of macrophages that induce an increase in the secretion of various proinflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL −6), plasminogen inhibitor 1 (PAI-1), C-reactive protein (CRP), and monocyte chemoattractant protein 1 (MCP-1), among others [11, 12].

The peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that plays a central role in the regulation of adipogenesis (differentiation and proliferation of adipocytes), allowing the expansion of the TAB in response to a positive energy balance through the increase in the number of small adipocytes with high sensitivity to insulin. In addition to this, PPARγ induces the expression of genes involved in uptake (lipoprotein adipocyte lipase (LPLa)), transport (CD6 fatty acid transporter (FAT/CD36), fatty acid-binding protein in adipocytes (aFABP)), esterification, and deposition of TG (acyl-CoA synthetase (ACS), perilipin 1 (Plin1)) and inhibits the expression of proteins involved in lipolysis (hormone-sensitive lipase (HSL), monoglyceride lipase (MGL)) [13, 14]. The above functions prevent the secretion of free fatty acids (FFA) into portal and systemic circulation and, consequently, lipotoxicity and insulin resistance in peripheral tissues. On the other hand, PPARγ contributes to maintain an adequate sensitivity to insulin through induction in the secretion of adiponectin (ApN) and leptin and the increase in the expression of the substrate of the insulin receptor (IRS1/2) and the transporter GLUT4 [15].

The oxidative function of WAT is generally underestimated. However, this is relevant during the process of differentiation of adipocytes in which the gene expression of PGC-1α is increased, a master regulator of mitochondrial biogenesis and oxidative metabolism [16].

The lipid droplets that are concentrated in the cytoplasm of adipocytes are surrounded by structural proteins and enzymes that respond to hormonal stimuli for lipolysis. Cyclic AMP (cAMP) is a second messenger that activates lipolysis by stimulating protein kinase A (PKA) which, in turn, is responsible for phosphorylating membrane protein perilipin 1 (Plin1). The latter activates the hydrolysis of the

**Figure 4.** *Lipogenesis stimulation by hypercaloric diets.*

### *Flavonoids: A Promising Therapy for Obesity Due to the High-Fat Diet DOI: http://dx.doi.org/10.5772/intechopen.84665*

TG stored in the lipid vacuoles through the induction of CGI-58, the coactivator of acyl triglyceride lipase (ATGL). Subsequently, PKA activates the hormone-sensitive lipase (HSL) that is responsible for hydrolyzing diacylglycerol (DAG) to monoacylglycerol, which will finally be hydrolyzed to obtain a non-esterified fatty acid (NEFA) and a glycerol molecule [10] (**Figure 5**)[55].

Insulin acts as a physiological inhibitor of catecholamine-induced lipolysis, since after stimulation of the insulin receptor (IRS-1/2) and phosphatidylinositol-3 kinase (PI3K), PKB is activated that phosphorylates phosphodiesterase-3B (PDE-3B) producing the hydrolysis of cAMP. The reduction of cAMP levels and PKB activity that accompany the activation of PDE-3B results in net dephosphorylation and decreased activity of HSL, leading to decreased hydrolysis of stored TAGs [56].

The adequate regulation of the process of lipolysis will lead to the fatty acids released into the circulation being captured by peripheral tissues, activated (addition of an acyl-CoA group), and transported, by carnitine palmitoyl transferase-1 (CPT-1/2), inside the mitochondrial matrix for its oxidation. However, the imbalance that is generated in the metabolism of adipocytes in obesity causes a lipogenic state and insulin resistance that decreases the rate of oxidation and favors lipolysis. The latter favors the ectopic deposits of lipids in the liver, a chronic state of inflammation and systemic resistance to insulin [10].

Abdominal obesity and IR in the WAT promote lipolysis and secretion of FFA into the portal circulation. In addition to this, an increase in plasma concentrations of remnant chylomicrons (rich in TG) is observed due to the absence of LPL induction in the liver and WAT. The hypertriglyceridemia is further accentuated by an increase in the synthesis and secretion of hepatic VLDLs, secondary to an increase in the portal flow of FFA and an increase in the production of apolipoprotein B-100 [17]. The hypertriglyceridemia of MS is directly related to a reduction in the plasma concentration of HDL and an increase in small and dense LDL particles (sdLDL) [18].

#### **Figure 5.**

*Control of lipolysis in the human adipocyte. Receptors β y α2A-adrenergic (RA), Kinase A protein (PKA), hormone-sensitive lipase (LSH), insulin receptor (IRS-1/2), Kinase B protein (PKB), kinase (PI3 [PI3-k]), phosphodiesterase type 3B (PDE 3B), kinase protein (PDK1), perilipin (Plin 1), diglyceride (DG), monoglyceride (MG), fatty acid transporter protein (FATP), free fatty acids (FFA), acyl co-A synthetase (ACS), Carnitine palmitoyltransferase (CTP), reactive oxygen species (ROS). The solid arrows indicate the effects that appear beyond the activation of kinases. The sign indicates stimulation and indicates inhibition.*

The decrease in plasma levels of HDL is the result of a decrease in the concentration of HDL3 particles (in maturation) and in a greater degree of HDL2 (mature). In hypertriglyceridemia, VLDL becomes prone to the reciprocal transfer of cholesterol esters and triglycerides with HDL2, by the action of cholesterol ester transferase protein (CPTE). This causes the conversion of HDL2 into smaller HDL3 particles rich in triglycerides that become suitable substrates for hepatic lipase (LH).

In IR, the greater induction of LH activity increases the hydrolysis of TG and phospholipids of HDL3 and promotes the formation of even smaller and poor HDL particles in cholesterol esters. They are more susceptible to renal dissociation and excretion of their apolipoprotein A-1 (apoA-1) [19, 20].

The decrease in plasma concentration of HDL reduces the reverse cholesterol transport (RCT) from the peripheral tissues to the liver for biliary excretion. As a result, the atherogenic processes and the elevation in total cholesterol concentrations are favored [19].

At the level of the pancreatic β cell, the accumulation of intracellular cholesterol (due to alterations in the ABCA1 cholesterol transporter) has been shown to influence the reduction of insulin secretion and cellular degeneration that culminates in apoptosis [21].

IR and decreased levels of HDL are related to an increase in sdLDL levels, which have a great atherogenic potential that increases the risk of developing CVD. Its formation is the product of an increase in CPTE activity that favors the exchange of cholesterol esters of LDL by TG of VLDL and consequently the formation of TG-rich LDL particles.

Skeletal muscle is another tissue that undergoes serious metabolic alterations due to the elevation of plasma FFA and TG levels, since it favors the uptake and excessive accumulation of TGIM that diminish mitochondrial oxidation capacity and contribute to the development of IR in this tissue [19, 20].

It has been suggested that the increase in intramyocellular accumulation of lipids is mediated by an increase in the translocation of the FAT/CD36 protein responsible for transporting long-chain fatty acids from the extracellular space to the outer mitochondrial membrane, where it favors its transport by the CPT-1 for its subsequent oxidation. However, when the uptake of fatty acids increases, there is a decrease in the rate of oxidation (by increased levels of malonyl-CoA that inhibit CPT-1) that promotes their accumulation in the form of TG drops. This is directly related to the development of IR and hyperglycemic states, since the accumulation of fatty acid metabolites (long-chain acyl-CoA, DAG, ceramides) induces kinase involved in the phosphorylation of amino acid residues of the insulin receptor or of its substrates resulting in the interruption of the insulin signaling cascade [20, 22].

#### **2.2 Cytokines secreted by fatty tissue**

Some of the cytokines secreted by fatty tissue are listed below:

Adiponectin: It is a protein that is synthesized mainly in adipocytes [23] and is the cytokine most secreted by adipose tissue. Its concentration is linked to the ADIPOQ gene [24] and is associated with inflammation processes.

Alpha tumor necrosis factor (TNFα): It is a cytokine that is associated primarily with the inflammatory response related to obesity. It also has an effect on lipid and glucose metabolism [25]. Studies have been conducted in humans with obesity showing high expression of TNFα in adipose tissue and a decreased expression of this factor after losing weight. It has also been shown that TNFα suppresses the transcription of adiponectin [26].

IL-6: It is a cytokine whose synthesis is induced by inflammatory stress and is involved in atherogenesis. It is believed that high levels of IL-6 are responsible for

### *Flavonoids: A Promising Therapy for Obesity Due to the High-Fat Diet DOI: http://dx.doi.org/10.5772/intechopen.84665*

the increase of proteins in obese patients, particularly CRP. This protein decreases the activity of lipases, which increases lipid consumption by macrophages. It has also been directly associated with IL-6 with the index of body mass, waist circumference, and visceral fat in obese patients [27].

MCP-1: It is a chemokine that is secreted in response to the proinflammatory cytokines that has the function of recruiting monocytes and macrophages in case of inflammation or tissue damage [28]. It is involved with obesity and is secreted by adipose tissue. Normally the adipose tissue of slender people contains 5–10% of macrophages, while in obese the content of macrophages in the adipose tissue can reach as high as 50% of the total cells [6].

PAI-1: It is an inhibitor of serum proteases whose main function is antifibrinolytic (the ability to promote the formation of clots). It has been discovered that this molecule is associated with the differentiation of pre-adipocytes to adipocytes, with the fat content in the vesicles of adipocytes and the level of leptin circulating in plasma [29].

Leptin: It is a hormone produced mainly by adipose tissue that is released into the bloodstream. Leptin levels decrease during fasting; after food intake, leptin is produced which sends a signal to the hypothalamus that inhibits the appetite [30]. However, it has been observed that in obese patients there is a phenomenon of resistance to leptin since in their blood high levels of this hormone have been found.
