**3. Metabolic disorders associated with obesity**

### **3.1 Organization of the adipose tissue**

Adipose tissue is a loose connective tissue in which about half the cells are adipocytes, the remaining is stromal vascular fraction containing preadipocytes, fibroblasts, endothelial cells, and macrophages [63]. The adipose tissue may be considered the largest endocrine gland in the body.

Based on the metabolic features of the adipocytes, adipose tissue (AT) can be white adipose tissue (WAT), which stores excess energy as fat, and brown adipose tissue (BAT), which dissipates stored energy as heat (**Figure 5**). Both WAT and BAT are present in mammals and are formed throughout life. In humans, WAT development begins during early to mid-gestation period. WAT adipocytes contain a large single (unilocular) droplet of triacylglycerols occupying 90% of the cell volume, with the cytoplasm and the nucleus squeezed to the periphery. Adipocytes of BAT are smaller, multilocular, and contain mitochondria and uncoupling protein-1 (UCP-1), which is involved in non-shivering thermogenesis. The brown appearance of BAT is due to high vasculature and high mitochondrial content. It has a high density of noradrenergic parenchymal fibers. BAT is 5–10 times more vascularized than WAT. A third type of adipose tissue, the beige or brite (brown in white) adipose tissue with paucilocular adipocytes is dispersed in the WAT [64–66]. Browning of WAT has been suggested under the influence

**Figure 5.** *Types of adipose tissue.*

*The Multiple Consequences of Obesity DOI: http://dx.doi.org/10.5772/intechopen.104764*

of the hormone irisin, which is produced by the skeletal muscle during exercise [67]. Adipocytes of WAT and beige adipose tissue are predominantly derived from the Myf 5 negative progenitor cells, while adipocytes of BAT are predominantly from Myf 5 positive progenitor cells. Myf 5 or myogenic factor 5 is a gene for transcriptional factor expressed during embryonic myogenesis [68]. Brown and beige AT show anatomical decline with aging and protect from obesity and type 2 diabetes mellitus (T2DM).

Based on the location of the white adipose tissue, it is broadly classified as subcutaneous and visceral (**Figure 5**). The subcutaneous adipose tissue (SAT) stores excess energy, provides insulation from heat and cold, and functions as an endocrine organ. Visceral adipose tissue (VAT) provides a protective padding around organs. Specialized adipose tissue is associated with the bone marrow, breast, retroorbital adipose tissue, and epicardium [69]. In persons having the same BMI, females tend to have more adipose tissue than males. Females also have more subcutaneous adipose tissue (SAT) compared with males. Localized fat pads, e.g., the synovia are considered as SAT. The SAT of lower trunk and gluteal-thigh region is further organized in two separate layers: the superficial SAT, SSAT (evenly distributed around the circumference of the abdomen), and the deep SAT, DSAT (most of which is located in the posterior half of the abdomen). The SSAT and DSAT are separated by the fascia of Scarpa. SSAT has a higher expression of metabolic regulatory genes, while DSAT has a higher level of expression of inflammatory genes and higher lipolytic activity. Thus, higher volume of DSAT is associated with higher levels of free fatty acids [70].

### **3.2 Specialized adipose tissue**

Bone marrow contains adipose tissue called the marrow adipose tissue (MAT), which increases in amount in periods of calorie restriction, in contrast to adipose tissue present at other sites in the body. Exercise results in decrease in the size of MAT, as well as of the adipocytes present in MAT. Adipocytes of MAT develop from the mesenchymal stem cells.

### **3.3 Diseases associated with adipose tissue**

In some persons there is a variable lack of adipose tissue, which may be generalized or specific (abnormal distribution of adipose tissue). This condition is called lipodystrophy. Lack of sufficient adipose tissue results in increased levels of fatty acids in blood, as they cannot be stored as TGs in the adipocytes. Raised levels of fatty acids cause lipotoxicity, characterized by ectopic fat deposition in the muscle, liver, and pancreas, thus contributing to T2DM [71].

### *3.3.1 Development of insulin resistance*

The mechanism of development of insulin resistance is complicated and is influenced by diverse factors, including the location and type of adipose tissue that increases in mass.

Depending on the location, WAT is further classified into different types (**Figure 5**) [72, 73]. Excess calorie intake leads to enlargement of adipocytes (hypertrophy) as well as increase in the number of adipocytes (hyperplasia) [74]. The new adipocytes may develop from preadipocytes or from adipocytes of BAT. Adipogenesis through differentiation of progenitor cells to adipocytes occurs through transcription factors such as peroxisome proliferator-activated receptor-γ (PPAR-γ), and CCAAT/enhancer binding protein-α [75]. Increase in the size of the adipocytes is associated with insulin resistance and inflammation. Adipose hypertrophy seen in morbid adiposity results in heterogeneity of cell size within the same depot of adipose tissue, with cell size ranging from 20 microns to 300 microns [76]. Usually, SAT contains more preadipocytes compared with VAT, so adipose hypertrophy is less in SAT [77]. Normal adipose tissue produces adipokines (leptin, adiponectin) that regulate appetite and energy metabolism and cytokines. Pro-inflammatory cytokines include TNF-α, visfatin, resistin, angiotensin II, serum amyloid alpha, plasminogen activator inhibitor, and IL-6, while anti-inflammatory cytokines include apelin, transforming growth factor beta (TGFβ), IL-10, IL-4, IL-13, and IL-1 receptor antagonist (IL-1Ra) [78]. Male hormones promote hypertrophy, while female hormones promote hyperplasia [79]. In lean adipose tissue, the adipose cells are 5–10% of all cells in the tissue; in obese adipose tissue, this number is as high as 60% [80]. Although the life span of adipocytes is about 8 years, increase in size beyond a critical cell size and nutrient excess produce endoplasmic reticulum stress, hypoxia, and death of adipocyte, attracting infiltration of macrophages. This is more in VAT. Adipocyte remnants are absorbed by macrophages, which become activated. In lean adipose tissue, the adipose tissue macrophages (ATMs) are predominantly M2 (anti-inflammatory) type. Pathologic adipose has greater number of M1 ATMs, which are pro-inflammatory and produce cytokines in large amounts after absorbing dead adipocytes. This results in chronic low-grade inflammation and insulin resistance.

In some persons with obesity, excess calories are preferentially stored in SAT, which does not produce inflammation. This type of obesity is also called metabolically healthy obesity (MHO) [81]. In contrast, increase in VAT is associated with abnormal blood lipid profile, i.e., dyslipidemia, insulin resistance, metabolic syndrome, type 2 diabetes, and hypertension. This type of obesity is called metabolically unhealthy obesity (MUHO) and is due to deposition of intraabdominal fat.

Hypertrophic stressed adipocytes are unable to take up free fatty acids, which are therefore diverted to other non-fat-storing organs such as muscle, liver, pancreas, and heart, where they are stored as ectopic fat. This results in impaired glucose uptake by muscle cells, decreased glucose utilization by liver and adipose causing hypertriglyceridemia, hyperglycemia, reduced amounts of HDL cholesterol, increased amounts of LDL and VLDL cholesterol, increased proportion of small, dense LDL particles, and insulin resistance. Products of fatty acid metabolism such as long-chain fatty acyl-Co A, diacyl glycerol (DAG), and ceramide are harmful to cells and aggravate insulin resistance by causing phosphorylation of the serine residues on the insulin receptor substrate (IRS) [82]. In skeletal muscle, lipid can be stored in adipocytes between muscle fibers, or as cytosolic triacylglycerols within the muscle cells (intramyocellular lipids, IMCLs). IMCLs are an adaptive response in endurance athletes and are present in close proximity to mitochondria. Increased IMCL stores in insulin resistance or T2DM is a consequence of raised free fatty acid levels in blood and impaired fatty acid oxidation in the muscle [83]. This may also be due to mitochondrial dysfunction.

Recent evidence suggests the role of leptin resistance and hyperleptinemia of obesity causes production of reactive oxygen species (ROS) and increases oxidative stress, promoting the risk of hypertension, heart disease, and cancer [84–86]. Endoplasmic reticulum stress, protein tyrosine phosphatase 1B, and suppressor of cytokine 3 (SOC3) signaling mediate leptin resistance and are also involved in insulin resistance [87].

## *3.3.2 Type 2 diabetes*

Insulin resistance in the liver, adipose, and muscles coupled with ectopic fat in the pancreas contributes to hyperglycemia and T2DM. Deposition of ectopic fat in the pancreas is seen in almost two-thirds of patients with obesity. Most of this is due to adipocyte infiltration into pancreatic tissue rather than accumulation of intracellular lipid. Ectopic pancreatic fat is associated with an increased risk of T2DM and cardiovascular disease (CVD). Increased lipolysis and inflammation caused by ectopic pancreatic fat are also reported to promote acute pancreatitis [88].
