Metabolic and Neurogenic Effects of Obesity: Implications for Chronic Diseases

## **Chapter 3** Metabolic Changes in Obesity

*Maritza Torres Valdez and Valmore José Bermúdez Pirela*

#### **Abstract**

The exact basis for the increase in global obesity rates is complex, so obesity should not be simply viewed as a biochemical problem of energy imbalance. While imbalance in energy metabolism is the main cause of obesity, only 5% of patients return to a normal weight after the incorporation of dietary changes. Eating behavior is enormously complex. It is governed by brain biochemistry influenced by many interdependent peptides or lipids. Excess body fat is the defining characteristic of this disorder, linked to the occurrence of a number of metabolic irregularities, which lead to other health problems. Adipose tissue plays an essential role in the metabolic process of energy balance, essential for understanding the phenomena associated with obesity.

**Keywords:** metabolism, obesity, food, energy, biochemistry

#### **1. Introduction**

#### **1.1 Definition of obesity**

Obesity has been defined and categorized by the application of body mass index (BMI), the most used indirect method to define and classify it, which is limited by its low specificity of 36–66% because this method does not allow to distinguish adipose tissue, as well as hydration index or fat mass. However, it continues to be widely used in all age groups because it is simple to apply and economic [1].

Pasca and Montero take a different approach [1]. They did not define obesity as an increase in adipose tissue, but evaluated it as a systemic pathology where various organs are involved, resulting in a deterioration of metabolism, characterized by inflammatory processes, expressed according to the relationship between the genome and the environment, where the phenotypic expression is acquired as a product of this interaction, mainly the increased deposition of adipose tissue [1].

#### **1.2 Ubiquity of adipose tissue**

Adipose tissue constitutes 20–28% of the weight in healthy people and 80% in obese people, depending on several factors such as sex, energy status, distribution, and location of adipose tissue that affect its function [2].

Preadipocytes, adipocytes, fibroblasts, macrophages, monocytes, vascular stromal cells, and innervating cells are among the variety of cell types seen in adipose tissue; however, most of these cells do not appear to be adipocytes [3]. Up to 80% of the DNA obtained from adipose tissue is derived from vascular cell, fibroblast, leukocyte,

and macrophage; three varieties of adipose tissue coexist according to function, color, vascularization, and structure [4].

As part of the connective tissue group, adipose tissue provides cohesion to organs or systems, supports structure, and is a key regulator of energy balance [5]. It is a complex endocrine tissue with high metabolic activity, and its function is to maintain energy balance, manage body temperature, regulate lipid and glucose metabolism, control blood pressure, and prevent blood clotting processes [6, 7].

Obese persons produce less elastin and more collagen types I, III, V, and VI, bronectin, and laminin in their adipose tissue than lean people [8]. These changes promote the growth of fibrotic tissue, which is more common in visceral fat than in subcutaneous fat [8]. Fibrosis, which favors lipid storage in the liver, pancreas, heart, skeletal muscle, limits the process of adipose tissue expansion. Collectively, these changes lead to lipotoxicity [8, 9].

Hepatic overload caused by fatty acid accumulation is the origin of increased hepatic gluconeogenesis and lipoprotein metabolism in hepatocytes, which also prevent the breakdown of insulin and apolipoprotein B [8, 9].

#### **2. Types of adipose tissue**

#### **2.1 White adipose tissue**

In each adipose cell of the target tissue there is a lipid vacuole, where lipids are stored for use when energy demand is required [10]. Triacylglycerols make up 90–99% of the total lipids in the vacuole and provide sufficient energy to meet the daily energy needs of an adult [10, 11].

White adipose tissue produces proteins with a wide range of functions in relation to immunity, proinflammatory cytokines, complement, fibrinolytic system, renin–angiotensin system, lipid mobilization, and steroid enzymes. It also produces large amounts of adipokines and lipokines, which act as metabolic regulatory hormones [2].

**Table 1** demonstrates the correlation between adipokines or lipokines produced with anti-inflammatory activity and those with pro-inflammatory and proatherogenic action in metabolic variations in obesity [12].

When there is an excess of energy, the functionality of adipocytes decreases, which is reflected in the imbalance of adipokine production [12]. Adipose tissue can buffer energy profusion through lipid storage is the result of proper expansion of this tissue, which is a sign of proper functionality [13].

Adipose tissue can develop through hyperplasia and hypertrophy and degenerate into malfunction with excess energy. This results in cardiometabolic risk leading to increased lipid deposition and decreased lipid utilization [5, 13].

#### **2.2 Adipocytes**

They are considered specialized cells that store lipids, but this is not their primary purpose, as evidenced by beta cells, muscle cells, and neurons [14]. Mature adipocytes develop when markers include the expression and adipocyte-associated hormones, cytokines, and enzymes associated with lipid storage and release into the bloodstream [14].


#### **Table 1.**

*Adipokines/lipokines, metabolic effect, and secretory organ or tissue.*

Perhaps the most interesting aspect of adipocyte differentiation is the way in which preadipocytes are added to the adipocyte repertoire, a repertoire of peroxisome-activated receptor family members and protein receptors that bind CCAAT enhancers [14].

Mature adipocytes are highly specialized cells that are central to energy storage and delivery mechanisms and are subject to very tight central and peripheral control, given these characteristics, it is not uncommon to find that adipose tissue is part of several axes, such as the adipose–insulin axis, the adipocyte–vascular–brain axis, and the adipocyte–myocyte axis [14, 15].

On another scale, the metabolic activity of adipocytes changes significantly in the hypoxia state. Indeed, some glycolytic enzyme genes, such as hexokinase 2 (HK2), phosphofructokinase (PFKP), and GLUT1, show increased expression in cultured adipocyte cells under hypoxia conditions. Moreover, while GLUT4 is the predominant isoform in adipocytes, GLUT1 is the most efficient glucose transporter at low oxygen levels. These changes suggest that adipocytes have increased glucose uptake and metabolism, as expected in hypoxic areas, which are supported by their increased secretion of lactate [15].

#### **2.3 Myocytes**

Myocytes are affected by obesity, while adipocytes slowly perish from asphyxia [15, 16]. The adipo–hypoglycemic axis plays a key role in obesity and accompanying diseases, such as type 2 diabetes, due to their mutual interaction. Under conditions of overfeeding, adipose tissue does not store excess energy in an adequate manner, resulting in a "spillover" impact on the entire body [15, 16].

#### **2.4 Adiponectin**

Adiponectin normalizes glucose metabolism and enables regulation of vascular homeostasis by interfering with key signaling pathways in the endothelial cells and reducing inflammatory activity in the subendothelial region. Adiponectin levels are often low in obese individuals, indicating that obesity, diabetes mellitus type 2 (DM2), and cardiovascular disease (CVD) are examples of insulin-resistant and inflammatory conditions that reduce the amount of insulin produced [17, 18].

Two receptors, AdipoR1 and AdipoR2, were initially cloned in 2003 by Yamauchi et al., modulate the actions of adiponectin [16]. Like the G protein-coupled-receptor (GPCRs) group, being an integral membrane protein with seven transmembrane domains. Adiponectin receptors, unlike GPCRs, have an internal N-terminal and an external C-terminal domain, both receptor subtypes can form homo- and heteromultinomers [18, 19]. In the pancreatic cell, high amounts of fatty acids (FAs) enhance the production of lipoprotein lipase, both receptors have been identified [18, 19].

#### **2.5 Brown or brown adipose tissue (BAT)**

This tissue in humans has metabolically active structures, and it consumes energy through thermogenesis to regulate body temperature [12]. It regulates energy balance by regulating metabolism. This is done by stimulating uncoupling proteins, and it uses proton flux from oxidative phosphorylation to produce heat, by activating betaadrenergic receptors in this tissue [20].

The brown adipocyte is a biological heat-producing powerhouse due to its unique ability to uncouple the process of oxidative phosphorylation and respiratory chain in its mitochondria [21]. As of the uncoupling protein UCP1, which renders the inner membrane of mitochondria proton permeable and causes brown adipocyte mitochondria to act as a metabolic substrate oxidation machine to produce heat rather than AT, this tissue is active in adults and abnormally inactive in obese people [21].

Differentiation in certain brown adipose tissue areas of white adipose cells, and increased activation of adrenaline and some cytokines promote trans-adaptive thermogenesis. This increases the expression of UCP1, the presence of brown and beige adipose tissue markers, enhances energy consumption, and promotes glucose tolerance [22]. The ability of brown and beige adipocytes to convert chemical energy into heat contributes to adaptive thermogenesis, a metabolic process whose metabolic function is correlated with a person's overall metabolic profile [22].

#### **2.6 Beige adipose tissue**

When experimental animals were exposed to prolonged cold to induce thermogenesis, beige adipose tissue (BAT) activation occurred with the development of brown adipose tissue at sites typical of white adipose tissue [23, 24].

*Metabolic Changes in Obesity DOI: http://dx.doi.org/10.5772/intechopen.110665*

Beige adipocytes that develop at the level of white adipose tissue have a completely different cell lineage than "traditional" brown adipocytes, according to several studies [25, 26].

Investigation of the browning process as a means of promoting BAT activity in the organism is of interest given this, along with the inducibility in the development of beige adipocytes in response to environmental variables [23, 24].

Following transdifferentiation, UCP1-expressing beige adipocytes can manifest in response to hormones, exercise, or cold exposure. These cells show a pattern of thermal gene expression that elevates energy and oxygen consumption [27]. Adipose tissue depots wait for environmental cues to become active, activating hormones such as leptin, FGF 21, and U2P (UF2) [3].

#### **3. Vasocrine regulation in pathological conditions**

Consistent with the plasticity of adipocytes observed in their preadipocyte differentiation into macrophages and hypertrophy/hyperplasia of differentiated adipocytes, the epicardial adipocyte also undergoes several changes [25]. Elevated synthesis of saturated free FAs, which bind toll-like receptor-4 (TLR-4) in macrophages and activate NF-kB, as well as increased TNF-α, are two modifications observed in larger adipocytes [25, 26]. However, macrophages may also develop from monocytes that spread through the subendothelial region via CAM-1 and MCP-1, rather than solely from differentiated preadipocytes [25, 26].

Most of the adipokines generated from adipose tissues have receptors expressed on blood arteries, which is crucial for cardiovascular pathology [28]. Proinflammatory adipokines are transported from epicardial fat to the vascular wall much more easily and efficiently due to the proximity of the epicardial adipose tissue (EAT) and coronary arteries. TNF from EAT readily diffuses into the blood arteries during RV by blocking the PI3K pathway in the endothelial cells [28].

In situations of insulin resistance, it has been confirmed that increased TNF-α locally induces a vasoconstriction related to ET-1 synthesis in coronary artery endothelium [25]. Together with the maintenance of chronic inflammation and insulin resistance in endothelial cells, this also plays a role. The extracellular signal-regulated kinase, which moves from the cytosol to the nucleus and triggers ET-1 production, is phosphorylated in this TNF-activated pathway [26, 28].

#### **4. Energy metabolism of obesity**

Imbalances in energy metabolism can lead to obesity [29]. In general, molecules that cause hunger tend to reduce energy expenditure, and compounds that cause satiety tend to increase the body's energy expenditure. This is because the basic mechanism of biochemical control of energy behavior is highly redundant and pleiotropic. This is congruent with the energy saving or energy expenditure tactics that the body uses depending on physiological and dietary circumstances [29].

According to Rial-Pensado et al. [30], the AMP-activated kinase enzyme plays a crucial role in this process by regulating brain-derived signals that regulate energy balance from the hypothalamus [30].

The malfunctioning of both cell typologies is due to an increase in white fat cells and a reduction in brown fat cells as a result of excessive energy intake [31]. The intervention of the immune system in adipocytes is crucial to maintain the balance in both tissues and favors the oxidation of FAs, which prevail in brown and beige cells [31].

It is important to understand these connections and the sequence of events that occur throughout the development of obesity [32].

#### **4.1 Obesity and energy balance**

The energy balance is neutral when these two variables are equal, i.e. balance between intake and expenditure; when there is an imbalance if the energy intake is greater than that expended, as with obesity, body weight slowly increases [33].

At the biochemical and physiological level, the many components of the energy balance equation are intrinsically related, so that alterations in one component of the equation may have a reverse effect on another; conversely, when food is restricted, as in the case of fasting, energy is conserved, and appetite is increased [33]. Despite these homeostatic reactions to preserve homeostasis, sedentary habits and/or chronic caloric excess can affect the efficacy of these regulatory mechanisms [33].

#### **4.2 Hypothalamic regulation of energy balance**

The hypothalamus is divided into nuclei or clusters of anatomically distinct neurons, which are linked by axonal projections to form neural circuits. The neuropeptides orexigenic, feeding promoter, agouti-related protein (AgRP), and neuropeptide Y are expressed by a cluster of neurons [34]. A second population of neurons expresses the anorexigenic products propiomelanocortin, which is the precursor of melanocyte alpha-stimulating hormone; these neurons project to other second-order neurons present in other hypothalamic nuclei [33].

The dorsomedial, lateral, and paraventricular nuclei are some of the secondary hypothalamic nuclei served by this group of first-order neurons, which send their axons widely to the central nervous system (CNS) [34]. The ventromedial nucleus of the hypothalamus, which is dorsal to the arcuate nucleus (ARC), receives mainly projections from AgRP/NPY and CART/POMC neurons. Axons from ventromedial nucleus (VMH) neurons also travel to the ARC, secondary hypothalamic nuclei, and brainstem areas [34].

#### **4.3 AMPK**

In eukaryotes, an enzyme known as an AMP-driven protein kinase functions as an energy sensor [35]. AMP-activated protein kinase (AMPK) is a heterotrimeric complex that exists at the molecular level. It consists of two regulatory and catalytic subunits that include serine/threonine protein kinase domains that are phosphorylated at threonine. The AMPK complex can exist in 12 different configurations in mammals because several genes are involved in the expression of each component [36].

#### **4.4 Hypothalamic AMPK as a regulator of ingestion**

ARC, paraventricular nucleus (PVN), VMH, and lateral hypothalamic area (LHA) are some of the hypothalamic areas where AMPK is expressed. The fact that AMPK modification is associated with insulin resistance, obesity, hormonal problems, metabolic changes, and cardiovascular disease serves as evidence of its physiological value [36].

Accordingly, fasting elevates hypothalamic AMPK activity, while refeeding inhibits it, acting as an energy sensor [37]. There is evidence linking hypothalamic

#### *Metabolic Changes in Obesity DOI: http://dx.doi.org/10.5772/intechopen.110665*

AMPK in the regulation of food intake. The orexigenic function of ghrelin is related to several findings on the hypothalamic role of AMPK in the management of energy balance [36].

#### **4.5 Hypothalamic AMPK as a regulator of thermogenesis**

Hypothalamic AMPK is involved in the control of brown adipose tissue thermogenesis by the CNS. Pharmacological and genetic studies demonstrate that VMH causes a decrease in weight and increase in the thermogenic program in the BAT in depletion of AMPK, the deduction of its activity, in response to thyroid hormones increases thermogenesis [34, 37].

#### **4.6 A regulator of glucose homeostasis: Hypothalamic AMPK**

These neurons are found in specific regions of the brain, including certain hypothalamic nuclei. Excess glucose inhibits the ability of the hypothalamus to activate AMPK, resulting in prolonged hypoglycemia. The ARC and VMH primarily control this impact. By fusing nutritional and hormonal information in the hypothalamus, AMPK functions as a crucial sensor in energy balance [36].

By accumulating altered lipid species that are "toxic," lipotoxicity affects cellular functioning as well as organs and tissues. Most of these lipid species have critical structural, signaling, or bioenergetic substrate functions that support the equilibrium state of the cell. However, harmful lipid derivatives can be produced by lipid species that are created as a direct result of chemical agents of reactive oxygen or nitrogen agents [36].

#### **4.7 Pathophysiological and metabolic changes in obesity**

Lipid reserve, prolonged inflammation, tissue hypoxia, endoplasmic reticulum (ER) stress **(Figure 1)**, and the emergence of insulin resistance constitute the physiological process of the development of overweight to obesity [38].

#### **Figure 1.**

*The endoplasmic reticulum (ER) is a central cell organelle in which transmembrane and secretory proteins are synthesized, folded and matured.*

The ER is a central cell organelle in which transmembrane and secretory proteins are synthesized, folded, and matured.

#### **4.8 Lipid accumulation**

Increased visceral and intra-abdominal fat is a sign of systemic fat deposition which triggers the production of cytokines that favor the onset of insulin resistance, inflammation, and development of cardiovascular pathology [31, 39].

#### **5. Lipoinflammation in obesity**

Adipose tissue has a significant impact on the inflammatory, antifibrinolytic, and vasoactive cascades, indicating that it has an immediate effect on the inflammatory process [38, 40]. Adipocytokines, which are elevated by hyperplasia, proliferation, and differentiation of preadipocytes, are the cytokines responsible for controlling the physiological response of adipose tissues [40].

The visceral fat depot expands with decreasing lipogenic capacity and by the process of hypertrophy, when the subcutaneous adipose tissue does not adequately store surplus energy exceeding the storage level [41].

The release of proinflammatory adipocytokines causes the macrophage scrolling inhibitor, IL-6 metalloproteinases, PAI-1, the vascular endothelial growth factor leptin [42]. Oxygen triggers cell death in the more peripheral fat cells, which transcribe into increased inflammation [42]. Hypoxia of adipose tissue is generated with death of peripheral adipocytes, transformation of M2 to M1 macrophages, angiogenesis, and increased production of inflammatory and anti-inflammatory proadipocytokines as shown in **(Figure 2)** [43].

This dysregulation is the result of adiponectin's disabling of NF-kB activation [43]. Macrophages located in obese adipose tissue alter and remodel with marked

**Figure 2.** *Source: Valmore Bermúdez.*

*Metabolic Changes in Obesity DOI: http://dx.doi.org/10.5772/intechopen.110665*

**Figure 3.** *Source: Valmore Bermúdez.*

heterogeneity in activity and function due to complex metabolic and immunological changes that vary according to the expression of specific antigens [43].

The phenomenon of a transient "phenotypic shift" from the primarily antiinflammatory M2 state of macrophage polarization to the more pro-inflammatory M1 form takes place during negative energy equilibrium [44].

The percentage of macrophages increased from 10–40% in the cells responsible for the release of proinflammatory chemicals, particularly TNF, in more than 50% of adipose tissue as shown in **(Figure 3)** [44, 45].

Metabolic and inflammatory processes are strongly connected and influence the progression of obesity, despite the fact that the mechanism of macrophage incorporation and adipose tissue filtration operate independently [45].

One of the most important indicators of subclinical inflammation is C-reactive protein (CRP) [46]. Regarding the regulation of macrophages, CRP has been related to M1 polarization, which is created in stimulating endothelial cells to produce M-CSF and activates NF-B [47]. Finally, since adiponectin is a hormone that promotes M2 polarization through AMPK, PPAR-, and PPAR-, low levels of adiponectin, as observed in the presence of visceral obesity, also favor M1 polarization [47, 48].

M2 polarization requires the attenuation of several mediators that promote M1 [49]. In this regard, the p50 subunit of NF-B has been found to inhibit NF-B-induced M1 polarization. Similarly, the complement protein C1q has been found to inhibit NF-B activation of macrophages during endocytosis and processing of lipoproteins, reducing the release of inflammatory cytokines [47, 49, 50].

As can be seen, macrophage polarization in each situation is a power play, the outcome of which is determined by the most common type of microenvironmental stimuli as can be seen in **(Figure 4)** [47, 50].

#### **5.1 Consequences of lipoinflammation**

Lipoinflammation involves a number of interconnected pathways that support and maintain obesity [51]. Chronic acceleration of proinflammatory pathways is one of the

key processes underlying the relationship between a chronic low-grade lipoinflammatory state, the emergence of insulin resistance, and development of comorbidities [52, 53].

According to the study, comorbidities, persistent low-grade lipoinflammation, and the occurrence of insulin resistance are related [53]. The maintenance of plasma insulin levels is known as hyperinsulinemia [53].

At the level of the CNS, insulin inhibits the action of leptin, promoting satiety and energy expenditure [51, 53]. The catalytic portion of the receptor is activated by binding to its transmembrane receptor heterotetrameric [51, 53].

To bind to more intracellular substrates and maintain signaling, the receptor undergoes autophosphorylation [54]. Phosphorylated tyrosine residues bind and phosphorylate various substrate proteins of the insulin receptor, allowing phosphoinosidase to bind and become active, thus connecting insulin signaling with neuronal firing rate regulation [51].

The signal transducer and transcription generator (STAT), which links insulin signaling to gene transcription of neurotransmitters responsible for appetite control and thermogenesis, is phosphorylated following phosphorylation of JAK-2 [51].

The hormone leptin is a part of the class I cytokine receptors lacking intrinsic catalytic activity. The JAK-2 enzyme binds to the leptin receptor forming a dimeric structure when bound to it, favoring the uptake of a second adjacent receptor unit [55].

A protein called STAT-3 is also recruited and phosphorylated, and it is this protein that is ultimately responsible for sending the leptin signal to the nucleus, controlling neurotransmitter transcription [55]. The signaling molecule involved in the anorexigenic effects of leptin is STAT-3, which regulates the transcriptional activity of numerous different genes [54, 55].

When SOCS3 is increased, it interacts with the leptin-JAK-2 receptor and disables leptin signaling [56]. The JAK-2/STAT-3 pathway is predominantly regulated by leptin in the hypothalamus, and insulin modulates this pathway [54]. There is a crosstalk in the insulin and leptin signaling pathways in the regulation of the satiety mechanism [55].

#### **5.2 Lipotoxicity due to lipid modification**

Some lipids play substantial roles in revising the catalytic activity of enzymes and their cellular localization, in addition to their structural and cell signaling functions, for example, by allowing translocation to the plasma membrane or the nucleus [31]. In describing the lipid modifications that determine lipotoxicity, we can also include modifications caused by the products of lipid peroxidation. In particular, we can focus on 4-hydroxynonenal, malondialdehyde and acrolein, which can mediate lipid elimination and, at the same time, have effects other than toxicity, such as the formation of amino acid side-chain conduits [31].

#### **5.3 Hypoxia and ER stress**

Obesity generates an increase in tissue irrigation, as the amount of adipose tissue directly affects blood flow [38]. In this situation, the aforementioned pro-inflammatory systems are activated, which is considered an aggression, favoring the reduction of blood flow and thus restricting the inflow of nutrients and unregulated tissue growth [38].

Nitric oxide is an important vasodilator of adipose tissue and is produced more frequently in hypoxic environments [57]. Anaerobic glycolysis is initiated, which releases energy in the form of ATP and changes the redox state of the cell, leading to a decrease in oxygen level, maintaining tissue hypoxia, and inducing acidification [57].

It generates dysfunction of mitochondria and ER, affects the insulin signaling pathway, and favors the secretion of proinflammatory cytokines in tissue [57].

The malfunction of protein production is called ER stress, also known as ER dysfunction. Due to a deposit of defective unfolded or misfolded proteins into the lumen of the ER or excessive protein production [58]. This response is triggered by any physiological or pathological circumstance that obstructs the ability of the ER to fold proteins. Inflammation and insulin resistance associated with obesity are closely related to UPR activation [58].

Adipocyte lipolysis is mediated by ER stress, by producing more IL-6 and less leptin and adiponectin, contributes to dysregulation of adipokine secretion [57, 58].

#### **6. Insulin resistance**

The increased blood glucose level causes the pancreatic islets of Langerhans to secrete insulin, which causes these tissues to take up more glucose. In addition, hepatic and muscle glycogen generation is enhanced by the process of dephosphorylation and activation of glycogen synthase [59].

Through activation of SREBP-1c, insulin exerts a hypogenic influence on lipid metabolism, promoting lipid synthesis and reducing lipid degradation. Insulin directly affects the expression, phosphorylation, and dephosphorylation of enzymes involved in gluconeogenesis and hepatic glycogenolysis [59].

Insulin resistance inhibits the body's ability to regulate blood glucose by reducing the cellular responsiveness to normal amounts of circulating insulin [60].

The insulin-signaling pathway is regulated by the insulin receptor, a tyrosine kinase that phosphorylates receptor substrates upon binding and activation. The expression, substrate binding, phosphorylation, and kinase activity of the insulin receptor can be modified [51].

Such phosphorylation can lead to the activation of the two major protein kinase signaling pathways, the mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) and serine–threonine Akt pathways, responsible for the arrangement of cell growth, gene expression, and protein synthesis and glucose uptake [51].

Excessive increase of lipids, triacylglycerol, saturated FAs in myocytes, promotes the synthesis of harmful lipid intermediates such as ceramides and diacylglycerols which have an adverse effect on insulin signaling, persistent inflammation, influences insulin signaling, where invading macrophages, release more TNF, thereby activating c-Jun-terminal kinase (JNK) and kappa-B kinase (IKK) signaling kinases promoting serine phosphorylation at IRS-1, favoring the onset of insulin resistance and type 2 diabetes [61].

#### **7. Metabolic stages of obesity**

In obesity, there are three metabolic stages involved in its development.

#### **7.1 Insulin control: gradual weight gain**

Insulin stimulates the production of glycogen, an energy store, and glucose oxidation at the hepatic level during the postprandial phase, producing ATP as an energy source and maintaining stable glucose levels between meals and during sleep. The liver uses a process called lipogenesis to convert the extra glucose into FAs [62, 63].

High-density lipoprotein transports the excess cholesterol to the hepatic level, where it interacts with nascent LDLV once in the blood (reverse cholesterol transport) [62, 63].

#### **7.2 Liver and adipose tissue metabolism under insulin control**

Adipose tissue: lipoprotein lipase (LPL) breaks down TGs into FAs and glycerol when mature VLDLs transport TGs into adipose tissue (the activity of this enzyme is insulin-dependent). As soon as the FAs enter the adipocytes, they are esterified with the help of glycerol phosphate, which is produced there by the glucose that was introduced by Glut-4 under the effect of insulin, then the liver receives the glycerol again [49, 51].

Adipocytes fill with TGs from the liver as they gain weight, even though the person is initially normoinsulinemic, normo-glycemic, and has normal lipid readings [49]. Depending on the level of adipose tissue storage, the duration of the "honeymoon" can vary adipogenesis, lipogenesis, apoptosis, and angiogenesis. This time span is short in people with low-lipid storage capacity; it is prolonged in those with high capacity. This process depends to a large extent on the anatomical compartment where the adipose tissue accumulates [62].

#### **7.3 Adipose tissue storage**

Adipocyte hyperplasia and adipocyte hypertrophy are inherited processes that affect the storage capacity of adipocytes [49].

#### **7.4 Molecular factors influencing body fat distribution**

Body fat distribution and total adiposity have an impact on systemic metabolism, and changes in either can increase the risk of metabolic pathology [63].

#### *Metabolic Changes in Obesity DOI: http://dx.doi.org/10.5772/intechopen.110665*

According to the amount of TG present, each anatomical depot has between 10 and 100 billion white adipocytes ranging in size from 10 to 200 microns [49]. The ability of the adipocytes in each depot to undergo hyperplasia and hypertrophy determines the amount of growth that each depot can support [49].

When the size of an adipocyte reaches a "critical" point where it can no longer expand, recruitment of preadipocytes occurs; the extent of this recruitment will depend on the pool of available adipocyte precursor cells. Adipocytes tend to evolve in both size and number over the course of growth [53, 63].

Subcutaneous adipocytes have a half-life of up to 10 years [53]. In addition to the recruitment of APCs and preadipocytes, the adipocyte undergoes continuous remodeling or turnover in which senescent and dysfunctional adipocytes are replaced by new differentiated adipocytes [53]. This continuous replacement is necessary because older adipocytes deteriorate, lose sensitivity to insulin action, and develop a proinflammatory phenotype [63].

It is believed that there are several interacting variables, which differ depending on the growth and age of the individual, resulting in epigenetic modifications that can be passed on from generation to generation, restricting the ability of adipocytes to grow and perform healthy remodeling [64].

Therefore, it can be assumed that a "metabolically ill" patient will have lower levels of APC, restricted adipocyte remodeling, less hyperplasia, and greater adipocyte hypertrophy, all leading to metabolic dysfunction [63]. On the other hand, regardless of the degree of obesity, a "metabolically healthy" obese person has more adipocyte hyperplasia in the abdominal subcutaneous depot, which is associated with metabolic health [63, 64].

#### **8. B. Insulin control vs. counterinsulin control**

When a person approaches the limit of storage capacity, they generate insulin resistance. Insulin levels are higher than physiological levels in maintaining blood glucose below 100 mg/dl, as defined by IR [63].

Adipose tissue develops insulin resistance (stage D) through upregulation of insulin receptors and increased sensitivity to hormones that act as counterinsulins (CI), including glucagon, cortisol, and adrenaline. These hormones trigger hormone sensitive lipase (HSL), an enzyme that controls the lipolytic process of TG breakdown [63].

Now that the partially filled adipocyte has room to store TG once more, insulin can activate LPL, causing it to fill with TG once more [63]. When the storage capacity of an adipocyte is exceeded, an inflammatory response is generated and the adipocyte releases cytokines that attract macrophages to the adipose tissue (stage F) [62, 63].

The TG overloaded adipocyte (stage A) undergoes morphological and functional changes and secretes resistin, infiltrating macrophages that produce TNF and other proinflammatory cytokines that permanently maintain the IR state, permanently slowing cell metabolism (stage C) [38].

Compensatory hyperinsulinemia is necessary to reverse the disabling of insulin action caused by -TNF and resistin, allowing the adipocyte to refill with TG (phase D). Plasma TG levels at this time may be normal, above the upper limit, or even only slightly above the upper limit [63].

#### **8.1 Perpetuation of insulin resistance in adipose tissue**

FAs created by lipolysis act on pancreatic beta cells, initially increasing insulin secretion. However, over time, they cause lipotoxicity by producing ceramides, which lead to cell deterioration processes by releasing cytochrome C from the mitochondria. As a result, pancreatic beta cells undergo apoptosis, which reduces insulin release. Reduced insulin secretion potentiates the influence of anti-insulin hormone, raising blood GA levels and increasing lipolysis, which affects skeletal muscle [62, 65].

GAs from hydrolysis of TGs exceed glucose from muscle glycogen storage because of palmitic acid, the fatty acid that accumulates most frequently [63, 65]. This limits the absorption of blood glucose from food and excess glycogen. Skeletal muscle glycogen stores remain full or partially full, making it difficult for the muscle to continue to absorb blood glucose from food, increasing postprandial glucose levels [66].

#### **9. C. Contrainsulin control**

TI impaired gluconeogenesis results in uncontrolled creation of glucose at the hepatic level from the amino acids created by the breakdown of protein [66]. Glucotoxicity and lipotoxicity in pancreatic β-cells culminate in β-cell apoptosis, which further reinforces the control of metabolism by insulin resistance. FAs are converted to acetyl-CoA through the process of beta-oxidation, in diabetic patients, and excessive and uncontrolled hepatic glucose synthesis elevates blood sugar levels [63].

This state indicates that the body is under the control of insulin-resistant hormones and uses FAs to provide energy to the liver in the absence of absolute or relative insulin [66]. FAs that are not β-oxidized by the liver is esterified by glycerol, coupled to apoB100 and transported into the blood. The reason for elevated plasma TGs in obese individuals with insulin-controlled reverse metabolism is that these large VLDL accumulate in the blood without their TGs being digested, and low levels of HDL cholesterol are another characteristic of obese people under insulin control [63, 67].

#### **10. Conclusions**

Obesity is defined as generalized increase in adipose tissue. It is a systemic illness which affects various body organs, resulting in metabolic deterioration, characterized by inflammatory processes, expressed according to the interactions between the genome and the environment, and manifest phenotypically as increased deposition of adipose tissue. Adipose tissue has the ability to buffer the surplus of energy through lipid storage through the expansion of this tissue, which is a sign of proper functionality.

Increased adipocytokines resulting from hyperplasia, proliferation, and differentiation of preadipocytes are responsible for controlling the physiological response of adipose tissue. When the subcutaneous adipose tissue does not adequately store the energy surplus due to exceeding storage capacity, the visceral fat depot expands with decrease in lipogenesis and increased adipocyte hypertrophy.

#### **Acknowledgements**

This work has been self-financed by the authors.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Metabolic Changes in Obesity DOI: http://dx.doi.org/10.5772/intechopen.110665*

#### **Author details**

Maritza Torres Valdez1 \* and Valmore José Bermúdez Pirela2

1 Ministry of Public Health of Ecuador, Climedic, Cuenca, Ecuador

2 Universidad Simón Bolívar, Cúcuta, Colombia

\*Address all correspondence to: torres.maritza78@yahoo.es

© 2023 The Author(s). Licensee IntechOpen. 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.

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#### **Chapter 4**

## Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function, and Neurogenesis

*Amina Khatun, Surendra Patra, Kuntal Ghosh, Shrabani Pradhan and Sudipta Chakrabarti*

#### **Abstract**

Obesity, a chronic condition that is currently prevalent in both developed and developing nations, is associated with pathological features that ultimately put individuals at risk for a number of negative health issues. Cognitive decline and insulin resistance are two aspects of metabolic syndrome that are closely linked to neurological dysfunction during obesity. Several studies suggest that obesity is associated with regional structural changes, especially signs of cortical thinning in specific brain regions like the hippocampus, and reduced microstructural integrity of the white matter tract is associated with an overall lower academic performance. Obesity causes a loss of brain size and volume indicating a loss of neurons which leads to poor cognitive performance and reduced neurogenesis. An increase in the production of free fatty acids seen with HFD eating might result in increased oxidative stress and increased production of reactive oxygen species. The main cause of systemic inflammation in obesity is the build-up of adipose as it releases TNFα, PAI-1, CRP, IL-1β, and IL-6 which contribute to a pro-inflammatory state in the central nervous system. These elements can all lead to the central IKK/NF-B inflammatory signalling cascade being activated, which can cause a vicious inflammatory cycle that quickens and causes neurodegeneration and cognitive decline.

**Keywords:** obesity, oxidative stress, inflammation, neurodegeneration, cognitive loss

#### **1. Introduction**

Overweight/obesity, a disease condition currently reaching epidemic proportions, particularly in industrialised countries, and linked to pathological changes that ultimately put people at risk for a variety of adverse health effects [1]. Obesity results from the accumulation of excessive body fat due to the consumption of excessive calories and is typically fuelled by western food habits and a sedentary lifestyle [2]. Food that has been processed and refined typically contains saturated fats, added

sugar, and salts, which over long-term contribute to increased calorie intake. There is much speculation and considerable debate about whether obesity-associated cognitive function is a result of weight gain, or whether it is a result of behaviours that lead to weight gain (such as hedonic overeating) [3, 4]. Body mass index (BMI) 25 and 30 are the World Health Organisation's (WHO) definitions of overweight and obesity, respectively [5]. Body mass index (BMI, kg/m2 ), which divides weight (kg) by height squared (m2 ), is widely used to determine obesity. Based on BMI, there are three categories: normal weight (BMI 18.5–24.9 kg/m<sup>2</sup> ), overweight (BMI 25.0–29.9 kg/m<sup>2</sup> ), and obese (BMI 30.0 kg/m<sup>2</sup> ).

However, metabolic syndromes arise when caloric intake significantly outweighs expenditure while there is a sustained lack of physical activity. The presence of low-grade metabolic inflammation in visceral adipose tissue is also considered to be a primary component of metabolic syndrome, which is characterised by central obesity [6]. The metabolic syndrome consists of a number of risk factors that contribute to chronic non-communicable disorders such as cardiovascular diseases (CVD), type 2 diabetes, dyslipidaemia and hypertension as well as other diseases. In addition to CVD, obesity has also been linked to pathological changes in brain morphology and function and cognitive impairments [7]. Even though the central nervous system (CNS) and the peripheral nervous system (PNS) have very different structures and functions, both are vulnerable to the deleterious effects of obesity, indicating that visceral adiposity may facilitate a common pathophysiologic mechanism. The metabolic syndrome includes components that are strongly associated with neurological dysfunction, such as insulin resistance and hypertension leading to cognitive decline. Such factors are generated by obesity. As a result, several processes may be working together to cause neurological dysfunction, while it can be difficult to determine the precise impact of visceral adiposity on neurological dysfunction. Animal obesity models' mechanistic insights reveal that excessive dietary fat impairs the hypothalamic coordination of energy homeostasis [8]. This pathway may be associated with the disintegration of adipose tissue, resulting in increased levels of free fatty acids, systemic inflammation and dyslipidaemia. As a consequence of chronic calorie overconsumption, circulating triglycerides increase and are adversely affected by numerous organs, including the liver. Dyslipidaemia caused by free fatty acids can result in neurological dysfunction because of lipotoxicity and altered intracellular signalling. Despite these mechanisms affecting the CNS and PNS in multiple ways, obesity is known to have neurological complications [9].

While wide range of functions in human brain requires significant energy, there are limited energy stores in the brain, and those stores can meet only a portion of its energy requirements. The blood-brain barrier (BBB) allows nutrients to continuously enter the brain from the blood, which is how the brain obtains the necessary energy for optimal functioning. Under physiological circumstances, the brain's primary fuel source is glucose [10]. During development, and at times when glucose supply is insufficient, the brain can use alternative energy substrates such as ketone bodies, triglycerides, as well as lactate [11]. Several recent studies have demonstrated that nutrition and dietary intake have a profound effect on cognition, neuronal function, neuronal signalling, and synaptic plasticity [12, 13]. The consumption of diets rich in saturated fats has consistently been linked to impaired cognitive function, both in clinical and preclinical studies [14, 15]. It is of interest to note that adult studies suggest that consuming high-fat diets (HFD) on a short-term basis may impair attention and memory capabilities [16, 17]. Remarkably, consumption of a diet high in saturated fats is frequently cited as a cause of the cognitive decline and

#### *Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

the development of Alzheimer's Disease [18]. Conversely, it has been suggested that diets high in polyunsaturated fatty acids enhance cognitive health Disease [18–20]. Depending on the composition, abundance, or lack of particular nutrients, the brain can be affected in different ways by different nutrient requirements. There is a known association between consuming saturated fat-rich diets and metabolic and cardiovascular diseases [21–23]. According to a growing body of research, obese individuals, and those with diabetes and with hypertension are at high risk of developing cognitive impairments and Alzheimer's disease [18, 24–27]. Since the global burden of both neurological diseases and metabolic disorders is increasing, it is necessary to investigate common underlying mechanisms associated with these rapidly increasing disease entities. In this article, we discuss how diet-induced overweight/obesity affect the function, neurogenesis and brain composure.

#### **2. Overweight/obesity: the pathophysiology**

In addition to storing energy and releasing it, adipose tissue serves as an insulation system for internal organs and a protection against trauma. Adipokines mediate the endocrine function of adipose tissue through hormones, cytokines, acute phase reactants, and growth factors [28]. These molecules play an important role in maintaining energy homeostasis along with the liver, pancreas, and brain. The major mechanism for achieving energy balance is via controlling energy intake and energy expenditure. Calories are truly calories, and they are all equal according to this fundamental energetic equation [29]. However, when we consider the pathophysiology of obesity-related comorbidities in addition to this merely energy balance aspect, we see that not all calories are created equal [29]. In order to properly explain the pathophysiology of obesity, two simultaneous discussions—one from an energy perspective and the other from a nutritional perspective—must be included. Here, we primarily concentrate on the second because there is controversy regarding the optimal nutritional composition, whereas there is significant agreement on the principles of energy balance management [6, 30]. Managing obesity-related diseases, such as CVD, requires a clear understanding of obesity-independent and obesity-dependent pathophysiologic effects.

Based on genome-wide association studies (GWAS), more than 140 chromosomal regions are associated with obesity [31]. The central nervous system has a significantly enriched gene expression profile associated with BMI and overall obesity [32]. Nevertheless, only a small number of genes, have been found to have a significant impact on BMI thus far. These are the paternally expressed genes along a specific region of chromosome 15 that cause Prader-Willi syndrome, as well as the genes that encode elements of leptin and melanocortin signalling [33]. Most researchers concur that environment, lifestyle, and genetic predisposition contribute to obesity predisposition [34]. Scientists generally agree that increased body weight or adiposity is actively regulated and mitigated by the body under constant environmental conditions, regardless of short-term perturbations in weight or adiposity [35]. Researchers have found that obesity is often defended as a disease, diverting blame from the person to the body's physiology, just as it is for normal-weight subjects [36]. In addition to adipocytes, adipose tissue contains stromovascular compartments, which are made up of nerve endings, blood vessels, preadipocytes, fibroblasts, endothelial cells, and resident immune cells [37]. As fat-storing cells, adipocytes store triglyceride-rich lipid droplets as a source of energy. Insulin is primarily responsible for regulating adipocyte energy uptake and storage, as it mediates fatty acid influx and lipogenesis while

inhibiting lipolysis [38]. When adipocytes are in a negative energy balance, sympathetic neural stimulation promotes lipolysis of stored triglycerides where fatty acids are delivered into the bloodstream to feed non-adipose tissues [39]. The adipocyte undergoes hypertrophy (enlargement of adipocytes) or hyperplasia (proliferation and differentiation) when there is a positive energy balance (i.e., excess caloric intake), it causes the adipocytes to expand in order to store excess calories.

Low-grade metabolic inflammation is associated with increased adipose mass, especially visceral depots, which promote metabolic disease as a consequence of malfunctioning adipose tissue. By increasing adipose mass, especially in visceral depots, metabolic inflammation is linked to metabolic disease, which occurs when adipose tissues malfunction [6]. Adipose tissue inflammation has negative effects on adipokine release, insulin signalling, triglyceride accumulation, and basal lipolysis, among other things. These alterations produce peripheral-tissue and nervous system dysfunction because they result in elevated levels of circulating adipokines and free fatty acids Smith [40]. A chronic caloric surplus that triggers stress signalling pathways and activates local macrophages causes metabolic inflammation, which mostly affects hypertrophied adipose tissue resulting overweight and obesity (**Figure 1**).

#### **3. The relationship between obesity and structural and functional changes in the brain**

Various structural changes in the brain can be measured by changes in brain volume or density. Several studies suggest that obesity is associated with regional structural changes, especially in elderly populations [41]. Researchers have reported reduced frontal lobe, anterior cingulate gyrus, hippocampus, and thalamus volume in cognitively healthy obese older individuals. Middle-aged adults and the elderly with high BMI have also been found to have impaired frontal lobe integrity [42–44]. The volume and density of the brain are often used as indicators of structural changes.

#### *Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

A growing body of evidence indicates obesity is associated with regional structural changes in obese populations, especially in elderly people [41]. The hippocampus, cingulate gyrus, and frontal lobes of obese older individuals were found to have reduced volume according to a tensor-based morphometry study [44]. Middle-aged adults and the elderly with high BMI have also been shown to have damage to their frontal lobes [42, 43]. The presence of obesity has been also linked to global structural changes in the brain, including an overall reduction in grey matter and white matter volumes [44].

Grey matter volume structural anomalies in obese patients were discovered by a recent systematic review [45]. The left middle frontal gyrus left middle temporal gyrus, left amygdala, and left cerebellar hemisphere all showed a consistent decline in grey matter in obese people when compared to the control regions, according to an analysis of 10 research published up to December 2017 [41, 43, 46–53]. A study by Kurth et al. found that the superior frontal gyrus on the left, middle and inferior frontal gyri, the right frontal pole, the left insula, as well as the bilateral superior and middle temporal gyri were negatively affected by body mass index [54]. According to García García et al., obesity and body mass are associated with significantly less grey matter volume in the areas of the brain that play a crucial role in executive control [55]. Obesity-related factors are consistently linked to decreased grey matter volume in a number of regions, including the left temporal pole, bilateral cerebellum, and medial prefrontal cortex. Similar to lean and overweight persons with increasing BMI, obese people have less total grey matter volume. Yokum et al., found that future weight increase is associated with a reduced amount of grey matter in the areas involved in inhibitory regulation [56]. Weight gain is primarily the result of abnormalities in the white matter volumes of the regional spine, not in the grey matter volumes, whereas abnormalities in grey matter volumes increase the likelihood of weight gain in the future.

Similarly, here is compelling evidence that people with increased BMI experience a brain-wide white matter decrease [57, 58]. The result is in line with a major investigation that found links between increased BMI and decreased white matter integrity in two separate, sizable populations [59]. Uncinate fascicle, internal capsule, corticospinal tract, inferior fronto-occipital fascicle, inferior and superior longitudinal fascicles, corpus callosum (cingulate gyrus and hippocampus), and cingulum are just a few of the white matter regions that are known to decrease with a higher BMI [45, 48, 50]. The critical limbic structures are connected to the prefrontal regions by local changes in the white matter fibre tracts linked to greater BMI, which may help to explain why obesity in older age is associated with an increased risk for cognitive impairments and dementia [60]. Obese people could age more quickly than average people, which is thought to raise the risk of cognitive impairment [61]. The fibre tracts that link limbic systems to prefrontal regions are the most commonly affected. These abnormalities are indicative of a loss of white matter integrity brought on by demyelination or inflammatory effects, and can be described by axonal injury or cellular death [61]. The bilateral thalamus, putamen, and globus pallidus in obese individuals are larger than those of normal weight, although the bilateral caudate is smaller [62]. Even obese people (with a BMI of 25 to 30 kg/m<sup>2</sup> ) have symptoms of basal ganglia atrophy and radiating crown [44].

Yau et al. [63] found evidence of cortical thinning in some areas of the brain and decreased microstructural quality of the white matter circuit in obese adolescents. In this study, obese youths performed no worse in cognitive tests than non-obese youths, but structural impairments were associated with a lower academic performance overall [63]. While these findings, do not prove causality, it is biologically conceivable to connect brain anatomical alterations to impaired cognitive function. Poor cognitive performance can be linked causally to smaller brain sizes and volumes since these changes are suggestive of a loss of neurons. Adolescents who are obese may show signs of brain abnormalities, but it may take them until later in life for these changes to cause cognitive impairment. In the early phases of cognitive decline, advanced brain imaging techniques that are more likely to detect anatomical micro alterations do not immediately translate into cognitive dysfunction [64]. As a result, it is particularly important to examine how obesity affects brain function by integrating physiological assessment with cognitive tests. Van Opstal [65] investigated the impact of weight loss (sustained fasting) on brain function in obese persons [65]. Fourteen subjects in this study met the BMI criteria for being classified as obese. During an overnight fast, a 48-hour fast, and an 8-week weight loss programme, brain imaging data were collected using whole-brain resting-state functional magnetic resonance imaging (MRI). The weight loss intervention, according to the researchers, decreased activation in the brain regions in charge of salience, sensory-motor control, and executive control, indicating a connection between weight loss and changes in neurological activity brought on by obesity [65].

A recent meta-analysis on anomalies in brain structure and obesity was undertaken by Opel et al. who also took into account the effects of ageing, hereditary risk, and psychiatric problems [66]. This study involved 6420 participants and examined the relationship between obesity (BMI > 30 kg/m<sup>2</sup> ) and brain anatomy. Results showed a strong relationship between obesity and cortical and subcortical abnormalities, particularly in the lower temporal-frontal cortex thickness. Cortical thickness was influenced by the combination of age and a higher polygenic risk score [66].

#### **4. Cognitive effects of diet-induced obesity/overweight**

Cognitive impairment can be caused by obesity when the physiology of the human energy system is impaired. In addition to affecting cognition and the Central Nervous System (CNS), obesity may also affect verbal learning, executive function, and decision-making [67]. An individual's cognitive function plays an important role in acquiring knowledge and information through the constant use of language, memory, and attention [68]. The effects of obesity on cognitive function can be attributed to structural and functional changes in the brain [69–71]. In executive functioning tests, obese females performed worse than normal-weight females. There was a reduction in grey matter volume in the left orbitofrontal region associated with a decrease in executive functioning [71]. Older people who are obese during midlife are more likely to develop dementia [72]. Several CVD risks factors, including obesity, T2D, dyslipidaemia, and hypertension, were demonstrated to negatively impact cognition in a systematic review [73]. According to studies, older women who have more body fat have poorer cognitive functioning [71].

#### **5. Childhood obesity and cognitive functions**

With childhood obesity is currently on the rise, deficits in attention and cognitive flexibility have been linked to childhood obesity [74]. According to cross-sectional

*Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

research on overweight children, overweight status was linked to worse test scores, particularly in the areas of arithmetic, reading, and executive function, while being physically fit was linked to better cognition performance, and behaviour [75]. Children who are overweight struggle with spatial cognitive tasks, and studies have revealed variations in both motor and mental rotation efficiency [76]. When rotation activities were challenging, overweight children made more mistakes than children of average weight [76]. Obesity can affect cognitive abilities, particularly executive abilities, in children and adolescents [77, 78]. According to studies, adolescents who are obese have lower executive and attentional cognitive abilities [79, 80]. Insufficient cognitive domains, including executive function and attention deficits, were found in obese adolescents in pilot research [79].

Data analysis from the general population revealed links between gender-specific features of developmental functioning with obesity and impairment [81]. Infants with high subcutaneous fat and children who are overweight or obese had delayed motor development [82]. It has been demonstrated that overweight children have significantly worse perceived and actual physical competence [83]. Overweight children had varying levels of difficulty with basic motor skills [84]. Compared to their peers who were of a healthy weight, obese children reported reduced degrees of gross motor function. The most significant variations were found in balance and locomotor abilities [85]. In comparison to children who were of a healthy weight, children who were overweight performed less effectively in the domains of intelligence, coordination, and gross motor abilities [86]. Significant abnormalities in gross and fine motor skills related to weight were observed in obese children [87].

#### **5.1 Possible mechanisms for cognitive impairment driven by diet-induced overweight**

#### *5.1.1 Role of oxidative stress on cognitive impairment*

The brain is thought to be the organ most susceptible to harm from oxidative stress [88]. This is explained by the greater lipid content, the high oxygen demand, and the scarcity of antioxidant enzymes [11]. Consistent overnutrition brought on by HFD diet may result in an abundance of reactive oxygen species (ROS) and reactive nitrogen species (RNS) [89]. Because of the excessive production of these species, macromolecules like DNA, membrane lipids, and protein structures are harmed [90]. Reduced glutathione, catalase, and superoxide dismutase act as endogenous antioxidant enzymes to neutralise these free radicals. A high fat diet causes excessive ROS production that exceeds the antioxidant enzymes' capacity [91].

Here, it is briefly mentioned how an HFD diet might leads to increased oxidative stress. HFD consumption results in an increase in free fatty acid production. In the normal diet-feeding process, electrons are transferred from cofactors (NADH and FADH2) to complex I of the mitochondrial respiratory chain, where they combine safely with oxygen and protons to form water [92]. Free fatty acids are then oxidised in the mitochondria through the mitochondrial respiratory chain. Superoxide radicals are created when some of these electrons interact with oxygen. Conversely, HFD feeding results in increased mitochondrial -oxidation of FFAs, resulting in increased levels of superoxide anion and an excess electron flow [92, 93]. The natural antioxidant enzymes can also be consumed by ROS, which increases the risk of oxidative injury to the brain [92, 94]. According to a growing body of research, the development of cognitive decline and increased oxidative stress may be correlated, [95–98]. These

findings suggest that increased oxidative stress is a major contributor to the cognitive abnormalities caused by HFD.

Many studies have demonstrated that HFD eating causes the levels of oxidative stress indicators in the brain to increase [99–104]. One of the most delicate areas of the brain to suffer from selective oxidative stress damage is the neocortex and hippocampal region. The impairment of cognition is also closely related to hippocampal oxidative stress [105–108]. Researchers have used antioxidant therapy to demonstrate cognitive benefits in support of the idea that oxidative stress may be a potential mechanism underlying the cognitive impairment associated with HFD eating. In HFD-fed mice, deficiencies can be restored by employing this strategy [99, 109, 110].

#### *5.1.2 Role of neuroinflammation on cognitive impairment*

Inflammation is controlled in a variety of ways by macrophages, depending on their differentiation level. Traditionally activated macrophages (M1) release proinflammatory cytokines and reactive oxygen species (ROS) to initiate an immune response, whereas alternatively activated macrophages (M2) reduce inflammation, promote tissue remodelling, and release growth factors in the later stages of an immune response [111]. Adipose tissue macrophages in healthy, nonobese humans appear to act similarly to M2 macrophages in that they contain arginase, which limits nitric oxide synthesis and promotes polyamine synthesis, and they release little to no proinflammatory cytokines [112]. Chemokine CCL2, formerly called monocyte chemotactic protein-1 (MCP1), is released by macrophages. TNF and IL-6 are also macrophage-released cytokines [113]. It is possible for M1 and M2 macrophages to coexist, which might result in fibrosis and prolonged inflammation [114]. Systemic inflammation in obesity is the result of build-up of adipose tissue and the increase in the levels of tumour necrosis factor-alpha (TNF-α), plasminogen activator inhibitor-1, C-reactive protein, interleukin-1-beta (IL-1β), and interleukin-6 (IL-6), Adipose tissue, particularly lymphocytes and macrophages, contains hypertrophic adipocytes and immune cells that contribute to inflammation [115, 116]. It is possible that processes of necrotic clearance are similar to inflammatory responses mediated by M1 in obese individuals [117, 118]. Macrophages release chemokines like CC-chemokine ligand 2 (CCL2; formerly known as monocyte chemotactic protein-1 (MCP1)) and cytokines like TNF and IL-6. Type 2 diabetes (T2DM) might result from interference in insulin signalling pathway in adipocytes caused by TNF and IL-6 [119]. Over time, macrophages build up in adipose tissue, and the cytokines they release can cause insulin resistance and T2DM [112, 113]. These inflammatory macrophages can increase atherogenic and CVD risks that are a feature of the metabolic syndrome associated with obesity by overexpressing procoagulant proteins [119].

#### *5.1.3 Effects of gut dysbiosis on obesity-related disorders*

Abnormalities in neurochemistry and inflammation may also be caused by the gut microbiota associated with obesity [120, 121]. The modification of the gut microbiota, or dysbiosis, can help to explain obesity since it is a factor that is central to host physiology and environmental stressors (such as diet and lifestyle) [120].

Gut dysbiosis (imbalance in gut microbiota composition caused by host genetics, lifestyle, and exposure to microorganisms) may facilitate diet-induced obesity and metabolic complications through a variety of mechanisms, including immune

#### *Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

dysregulation, altered energy regulation, altered gut hormone regulation, and proinflammatory mechanisms (such as lipopolysaccharide endotoxins that cross the gut barrier and enter the portal circulation) [121–123]. Recent studies have indicated that changes in the composition of the gut and inflammation brought on by a leaky gut may have an impact on the pathophysiology of many disorders, such as depression, chronic fatigue syndrome, obesity, and type 2 diabetes (T2DM) (a loss of intestinal barrier integrity that reduces the ability of the gut to protect the internal environment) [124].

Obesity-related inflammation can impact the amygdala, cerebral cortex, hippocampus, and brain stem [125]. Numerous routes, including alteration of the blood– brain barrier (BBB) and choroid plexuses, have been used to link obesity-related low-grade inflammation to neuroinflammation [126]. Insulin resistance is caused by peripheral inflammation, which is seen in obesity [112, 113]. Although it is widely acknowledged that the brain plays a special role in immunity, there have been some instances of transitions between peripheral and central inflammation. It is also possible to express adipokines in the CNS, where these factors have receptors. Adipose tissue produces adipokines, which are expressed in the CNS as well. Peripherally produced adipokines can influence the CNS by crossing the BBB or changing its physiology by interacting with the cells that make up the BBB [127]. There is a strong correlation between neuroinflammation and oxidative stress and a wide range of chronic neurodegenerative diseases [128]. These processes can be regulated by adipokines. Inflammation in the brain can also result from damage to the BBB with ageing [129]. The most significant contributor to cognitive dysfunction may be neuroinflammation, which might also act as a primary pathogenic mechanism for ageing [130].

There is a connection between the activation states of cytokines and chemokines produced by different cell types in adipose tissue outside the central nervous system (quiescent or activated). Obesity and neurodegeneration are linked via the production of inflammatory cytokines and resistance to insulin-like growth factor 1 (IGF-1) [115, 116, 128, 130, 131]. As a result of central inflammation in obesity, hypothalamic satiety signals are interrupted, which perpetuates overeating and has negative consequences for cognition [132]. Different disorders associated with ageing are also thought to be influenced by chronic inflammation. Peripheral inflammation and associated metabolic abnormalities promote T2DM, insulin resistance, and neurodegenerative diseases [133]. In the abdominal adipose tissue, macrophages promote the synthesis of cytokines and proinflammatory chemokines that can cross the BBB. Interferon-gamma can activate microglia, which then serve as relays for neuroinflammation [134].

A number of pathological mechanisms are exacerbated by hypertension, diabetes, and obesity, including cerebral hypoperfusion and glucose hypometabolism. Neuroinflammation and oxidative-nitrosative stress are triggered by these risk factors. There are several cycles of pathological feedback caused by proinflammatory cytokines, endothelin1, and oxidative-nitrosative stress [135]. These cascades cause neurodegeneration and an increase in neuronal Ca2+ [60]. Long-term damage to mitochondria, proteins, DNA, and fatty acids is promoted by oxidative-nitrosative stress. These elements magnify and sustain a variety of problematic feedback loops [136]. Chronic cerebral hypoperfusion results from dysfunctional energy metabolism (compromised mitochondrial ATP production), formation of -amyloid, endothelial dysfunction, and modification of the BBB [115, 130]. Hypoperfusion deprives the brain of oxygen and nutrition, which are its two most critical trophic factors. As a result, the brain experiences synaptic dysfunction and neuronal death,

which causes grey and white matter atrophy [136]. The decline of M2 macrophages in the CNS is associated with many neurodegenerative diseases and the subsequent increase of M1-induced inflammation [134]. Microglia and macrophages express the macrophage-stimulating protein receptor (MST1R). In the periphery, obesity-mediated inflammation is attenuated by activating MST1R with its ligand, a macrophagestimulating protein. Cleavage to the MST1R ligand in vivo regulates the activation of macrophage-dependent repair (M2) [137]. Apoptosis can be caused by neuroinflammation [138]. Its fundamental physiological function, which helps to maintain homeostasis, is a tightly controlled process of cell death. A variety of proteins, signal transducers, and signalling pathway cascades collaborate to fully implement apoptosis [139]. Numerous disorders' origin and/or progression are strongly correlated with poor apoptotic regulation [138, 140]. TRAIL, TNF, and Fas ligand (Fas-L) bind to the extracellular domain of DR (transmembrane receptors) to initiate the TNF pathway, the main apoptosis pathway [138–140]. During an inflammatory response, TNF- and Fas-L can cause certain neurons to apoptose [138].

Caspases, which are cysteine proteases, are activated during apoptosis, which controls all of the morphological changes that distinguish this type of cell death [138]. Activating effector caspases (caspases 3, 6, and 7) via a controlled, irreversible, and self-amplifying proteolytic route begins with activating initiator caspases (caspases 2, 8, or 10) [141].

#### **6. Obesity and impaired neurogenesis**

It has now been proven beyond a shadow of a doubt that neurogenesis takes place in specific parts of the adult brain, debunking the long-held belief that brain cells lack any capacity for regeneration [142]. Neuronal stem cells (NSCs) in the CNS of adult mammals may now be isolated and identified toas a result of advances in science and technology. Even though adult neurogenesis was first observed in the 1960s, multiple articles have argued that adult mammalian brains do not show any indications of neurogenesis [143–145]. Adult hippocampal neurogenesis in mammals, including rodents was not "rediscover[ed]" for another three decades [146, 147]. When these freshly produced cells' "stem-like" properties were first identified in the 1990s, it was believed that NSCs could auto replicate and give rise to a variety of neural lineages in adult mammalian brains, including neurons, astrocytes, and oligodendrocytes [148–150]. Later research showed that NSCs were mostly found in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the hippocampus dentate gyrus in the adult central CNS [151]. The functional integrity and plasticity of these brain regions are thought to be maintained by these adult NSCs by initiating neurogenesis in response to intrinsic and extrinsic changes, which is consistent with the observation that neurogenesis was also highly prevalent around these regions in adult mammalian brain [152]. Recent research indicates that multipotent NSCs, which have the capacity to differentiate into new neurons as well as astrocytes and oligodendrocytes, can be reprogrammed to grow in the adult mouse hypothalamus in the medio basal region of the hypothalamus (MBH) and the third ventricle wall [153]. These newly formed neurons in the adult mouse hypothalamus could integrate into the existing neuronal network and have recently been shown to be functionally active [154].

Several decades ago, neurogenesis in the adult brain was considered impossible and was refuted, but it has now been widely acknowledged as a very common phenomenon [146, 148]. Many brain regions are abundant in new neurons and NSCs [146].

#### *Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

The hypothalamus, which houses the body's neuroendocrine system, has recently been found to be both a rich NSC niche and a hotspot of neurogenesis [153]. It is believed that these hypothalamic NSCs play a key role in the neuroendocrine modulation of whole-body physiology [155–157] as well as systemic ageing [158]. Through local or extrinsic insults to this hypothalamic region, disruption of their neurogenic function may lead to neurodegenerative manifestations across the neuronal milieu. A specific condition known as neurodegeneration, the loss of cognitive abilities, and hypothalamic stem cell damage, as well as obesity and chronic energy imbalance, have been reported to occur after chronic inflammation or inflammation induced by overnutrition or ageing. Additionally, there is data linking brain diseases to overnutrition. Neuroinflammation is clearly to blame for poor neurogenesis and NSC depletion [159]. Furthermore, chronic inflammation slows neurogenesis, NSC survival, and differentiation, and increases ageing-related decline and neurodegenerative disorders [158, 160–163] despite providing a necessary defensive mechanism for the body. IKB kinase (IKK) and its downstream nuclear transcription factor NFκB (IKK/NFκB signalling) are part of the proinflammatory axis in the hypothalamus that is exacerbated by overnutrition [60, 164]. It has been found that overeating and age-related activation of the IKK/NFκB signalling pathway all contribute to obesity, chronic energy imbalance, neurotoxicity and cognitive impairment 21, and hypothalamic stem cell degradation [164–169]. A connection between overnutrition/ageing-induced neuroinflammation and neurodegenerative diseases is further supported by evidence and implications relating to overnutrition-induced neurological diseases including Alzheimer's (AD) and Parkinson's (PD) [170–173].

While neuroinflammation is an important defence mechanism in reaction to infections, illnesses, and brain damage, persistent inflammation compromises the body's normal defences and promotes the progressive neurological and neurodegenerative illnesses [160–163]. Additionally affected by neurological conditions and disorders, adult neurogenesis is severely impacted by inflammation [174]. For instance, neuroinflammation has been shown to inhibit neurogenesis in the adult hippocampus; neurogenesis may be restored if inflammation is blocked [159, 175]. Adult mice kept on a protracted high-fat diet (HFD) exhibit markedly reduced neurogenesis in the hypothalamus which may also be due to neuroinflammatory reactions generated by the HFD [176, 177]. Contrarily, short-term HFD intake can result in an increase in hypothalamic neurogenesis, which is most likely an adaptive response of the hypothalamus to offset the detrimental effects of HFD feeding on energy balance [176]. The proliferation and differentiation of htNSCs generated from obese mice were shown to be hindered by Li et al., in their study. Such contortion resulted from the overproduction of inflammatory cytokines such TNF- and IL-1, which are known to potently activate IKK/NFκB and were created as a result of NFκB activation, leading to the activation of an inflammatory axis with a positive feed-forward loop [153]. IKK/NFκB activation significantly reduced in vitro htNSC survival, differentiation, and neurogenesis, while IKK/ NFκB pathway inhibition increased htNSC survival, differentiation, and neurogenesis, providing additional and direct evidence of the harmful consequences of inflammation [153].

Even while it is established that hippocampal neurogenesis plays a crucial role in appropriate hippocampus function, learning, and memory, there was some scepticism about the report [178–180]. Two recent investigations, focusing in particular on the limited population of Pro-opiomelanocortin (POMC) neurons that play essential roles in regulating energy balance, showed that chronic HFD-induced obesity and

#### **Figure 2.**

*Possible mechanism of obesity and cognitive dysfunction.*

leptin deficit in mice resulted in a reduction in the adult NSC population and new neuron turnover [153]. Through the activation of multiple pro-inflammatory cascades, including the IKK/NFκB inflammatory axis, chronic HFD eating induces metabolic inflammation in the brain, particularly in the hypothalamus. Li et al. showed that chronic HFD eating in mice resulted in both htNSC depletion and neurogenic dysfunction linked to IKK/NFκB activation. The chronic consequences of metabolic dysfunctions, such as excessive calorie intake, glucose intolerance, insulin resistance, and obesity, were discovered in mice that had been genetically modified to have less NSCs in the MBH (**Figure 2**) [153].

#### **7. Diet-induced obesity and synaptic plasticity dysfunction**

The ability of the nervous system to dynamically modify its function in response to ongoing internal processes or outside events is referred to as the nervous system's plasticity [181]. It is a normal and important aspect of cognition as well as a key method through which the brain can heal after damage [182]. From fundamental physiological processes to integrated behavioural responses, plasticity can be understood and defined at many distinct levels of function [183, 184]. The physical morphology of synapses is related to structural plasticity [185]. Recent research has indicated that the HFD diet, which contains between 47 and 70% fat, has an impact on the brain's cognitive function [186–194]. According to this research, HFD causes negative consequences in various brain regions, including the hippocampus, via activating signalling pathways [195, 196]. HFD may have deleterious effects on memory and mood because it alters the systems that control synaptic transmission and the production of proteins associated with plasticity. HFD also causes obesity, which has an impact on the cellular and molecular mechanisms underlying synaptic plasticity in the brain, which impacts learning, memory, and mood. HFD also impaired brain-derived neurotrophic factors (BDNF), and amyloid precursor protein (APP) in the hippocampus.

#### **7.1 Effects of obesity on BDNF**

Neuroinflammation in the brain is a significant contributor to the development of neurodegenerative diseases. BDNF has the ability to regulate it [197]. This protein is

*Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

required for the proper functional development of brain structures as well as the development and retention of synaptic transmission [198]. In addition to its conventional neurotrophic roles, BDNF also seems to have neuroprotective properties against a number of brain traumas, including as ischemia, traumatic brain injuries, and Alzheimer's disease [199]. It also significantly contributes to the metabolism of energy by reducing food intake, limiting weight gain, and enhancing locomotion following intracerebroventricular injection [183, 200]. Through molecules like synapsin I and growth-associated protein 43, BDNF can control neural plasticity [201, 202]. Synapsin I promotes BDNF modulation of synaptic vesicle exocytosis of neurotransmitters in addition to stimulating axonal growth and supporting synaptic connections [203]. It has been demonstrated that BDNF activation results in synapsin I phosphorylation [204, 205]. According to studies HFD consumption impairs hippocampus synaptic plasticity and cognitive capacities by regulating BDNF expression [206–209]. Other research has shown that HFD raises brain oxidative stress, which stimulates neuroinflammation and lowers levels of BDNF [186, 210]. After 4 months of HFD ingestion in mice, decreased levels of the basic synaptic proteins SNAP-25 and post-synaptic density (PSD)-95 may increase the brain's vulnerability to the negative effects of HFD [186].

#### **7.2 Effects of obesity on APP**

The biology of APP may have a role in the association between obesity and cognitive performance [211]. APP can be converted into the two peptides Ab1-40 and Ab1-42 by the brain's neurons, where it is mostly synthesised [212]. Amyloid plaques, a component of AD, are produced when both types of peptides are together [213]. Recent research suggests that the pathophysiology of obesity may also be influenced by APP expression or function [214]. The expression of APP in adipocyte cell lines and adipose tissue has been documented [215, 216]. More significantly, obese people have elevated plasma levels of adipose APP and Ab1-40 [216, 217]. Studies have shown that greater cholesterol levels induce higher amounts of amyloid- in both AD-transgenic and low-density lipoprotein receptor-deficient animals after 8 weeks of diet-dependent obesity in mice [214, 218, 219]. The APP expression or function modifications may be coordinated between several tissue types [214]. In contrast to visceral and subcutaneous fat, one study demonstrated variations in APP expression in brain cells [193]. Inflammation, macrophage and adipocyte phenotype, and macrophage and adipocyte culture phenotype were examined for comparison with the in vivo changes [193].

Another study discovered that feeding mice a very high-fat diet (HFD) for 5 weeks lowered the amounts of the cytoskeleton-associated protein (Arc), which controls baseline activity, in the cerebral cortex and hippocampus. The latter mice developed brain insulin resistance, and acute insulin stimulation reduced phosphatidylinositol 3-kinase (PI3K)/protein kinase B/p70 ribosomal S6 kinase pathway activity, which in turn reduced activation of Arc protein expression [193].

#### **7.3 Effects of obesity on microglia**

In addition to driving the inflammatory response in response to various stimuli, microglial cells also regularly maintain neurotrophic connections by remodelling and optimising synapses [220]. Microglia are said to react to neuroinflammation by releasing several kinds of macrovesicles [221]. For instance, when lipopolysaccharide activates BV2 microglial cells, the pro-inflammatory cytokines tumour necrosis factor and interleukin-6 are released [222]. Immature dendritic spine pattern in CA1

diIlabeled neurons, which showed decreased neurogenic ability and lower levels of the scaffold protein Shank 2, suggest impaired connection following an HFD (60% fat) [223]. The medial prefrontal cortex, a part of the brain crucial for cognitive flexibility, exhibits abnormalities in microglial morphology, synapse loss, and cognitive deficits in early-stage obese rats [189]. Additionally, it enhances synaptosome internalisation and microglial activation [191]. Mice given a 60% HFD were found to have fewer dendritic spines, higher levels of microglial activation, and higher levels of synaptic profiles within the microglia. Additionally, transgenic and pharmaceutical techniques that block microglial activation shield obese animals from cognitive deterioration and dendritic spine loss. Additionally, pharmaceutical reduction of microglia's phagocytic activity has been found to be adequate to stop cognitive decline [224].

#### **7.4 The role of insulin receptors in memory**

A crucial part of controlling body metabolism is insulin. However, insulin modifies neural activity, strengthening synaptic connections and increasing memory function [225–227]. Insulin is known to have profound effects on neurotransmission [228]. PSD fractions contain insulin receptors, which are heavily concentrated in synaptosomes [229]. The scaffolding proteins shank and PSD-95 may also interact with them through insulin receptor tyrosine kinase substrate IRSp53, which is colocalized with synaptophysin and synapsin 1 [230, 231]. Neurites are promoted by insulin, catecholamine release and uptake is regulated, ligand-gated ion channel trafficking is controlled, gamma-aminobutyric acid, N-methyl-d-aspartic acid (NMDA) and AMPA receptors are expressed and localised, and NMDA and PI3K-Akt are involved in modulating synaptic plasticity [232]. There has been significant evidence that insulin resistance and the metabolic syndrome may cause cognitive impairments through mechanisms such as IPMK-mTOR/Akt, synapto-dendritic molecular neuroanatomy, and spatial working memory [233]. In mice, diets high in fat lead to insulin resistance in the cerebral cortex and hypothalamus. Several animal models have shown that insulin resistance affects cognition-related circuitry and neurotransmission [187, 226].

Studies in animals have found reduced dendritic spines in CA1 as well as impairments in long-term memory associated with HFD feeding [191, 234, 235]. Many different parts of the brain can be negatively impacted by alterations in glucose homeostasis, but the hippocampus is particularly susceptible to them [236–238]. According to research by Strahan et al., rats fed a high-fat, high-glucose diet for 8 months showed significant impairments in their hippocampal dendritic spine density, spatial learning ability, and LTP at Schaffer collateral-CA1 synapses [239]. In addition, high-fat, high-glucose-fed animals showed a reduction in BDNF levels in the hippocampus compared with controls. They suggested that the changes could be due to peripheral insulin resistance, or that some components of the diet may directly affect brain health and hippocampal plasticity. Further evidence suggests that the DG of rats fed HFD exhibit impaired stimulus-evoked LTP [240]. HFD feeding leads to a change in the expression of protein-coding genes in the cortex, but studies have not explored alterations in non-coding RNAs. The HFD feeding of mice led to changes in both coding and non-coding RNA expression in the brain cortex, according to a study by Yoon and colleagues. According to these researchers, consuming HFD for 8 weeks causes a decrease in the expression of genes linked to synaptogenesis and neurotransmitter release [241]. In the hippocampus of animals receiving HFD, Arnold,

*Diet-Induced Overweight Conditions: Effect on Brain Structure, Cognitive Function… DOI: http://dx.doi.org/10.5772/intechopen.110610*

and colleagues likewise found that PSD-95 expression was downregulated [187]. Interesting investigations have found that animals given the HFD have less neurogenesis in their dentate gyrus [242]. Thus, it is clear that HFD may significantly modify the expression of many genes linked to these processes, which may have a negative impact on brain morphology and synaptic plasticity.

#### **8. Conclusion**

Obesity is a serious public health problem that is increasing an proportions with serious health and societal problems. It mostly affects cognition through changing the structures and operations of the brain. Brain structure, leptin/insulin dysregulation, oxidative stress, cerebrovascular function, blood-brain barrier, and inflammation are all impacted by obesity and contribute to the decline in cognitive performance. Inhibition of neurogenesis is thought to be caused by neuroinflammation, which can be brought on by a variety of internal or external factors, including ER and oxidative stress, as well as, overnutrition-induced metabolic inflammation, and autophagic defects. These factors are all connected to the activation of the central IKK/NF-B inflammatory signalling cascade, which can result in a vicious inflammatory cycle that accelerates ageing, neurodegeneration, and cognitive decline.

#### **Author details**

Amina Khatun1 , Surendra Patra1 , Kuntal Ghosh1 , Shrabani Pradhan2 and Sudipta Chakrabarti1 \*

1 Department of Biological Sciences, Midnapore City College, Kuturiya, Bhadutala, Paschim Medinipur, West Bengal, India

2 Department of Paramedical and Allied Health Science, Midnapore City College, Kuturiya, Bhadutala, Paschim Medinipur, West Bengal, India

\*Address all correspondence to: sudiptadna@gmail.com

© 2023 The Author(s). Licensee IntechOpen. 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.

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#### **Chapter 5**

## Obesity: A Prerequisite for Major Chronic Illnesses

*Hafeez Abiola Afolabi, Zaidi Zakaria, Salzihan Md. Salleh, Ewe Seng Ch'ng, Siti Norasikin Mohd Nafi, Ahmad Aizat Bin Abdul Aziz, Sameer Badri Al-Mhanna, Ahmad Adebayo Irekeola, Yusuf Wada and Abubakar Bishir Daku*

#### **Abstract**

Obesity is rampantly soaring at an alarming rate globally and simultaneously causing an increased incidence, and predisposition to various comorbidities. obesity is body mass index of >30kg/m2 , while <18kg/m2 is underweight. The world at large fails to recognize obesity as an inevitable disease that requires strict measures to control this modifiable risk factor. W.H.O news release reported that over one billion people globally are obese among which 650 million were adults, 340 million were adolescents, and 39 million were children. The lowest obesity prevalence was reported in Timor Leste at 3.80%, Bangladesh at 3.60%, and Vietnam at 2.10% while the highest were noted in Nauru at 61%, cook island at 55.9%, and Palau at 55.3%. obesity is the most prevailing health problem (15% globally) associated with an increased propensity for development of several medical illnesses, obesity-associated adverse outcomes causing fatal complications that are difficult to manage, and premature mortality. The obese often feel they are not socially cared for by society and are accorded limited time by physicians who don't view their health concerns from their own perspectives. Thus, making them pessimistic from low self-esteem and discrimination, body shaming, and stigmatization. They eventually develop depressive-anxiety disorder because of distrust insight.

**Keywords:** obesity, overweight, body mass index (BMI), comorbid, chronic diseases, obesity prevalence

#### **1. Introduction**

Obesity is exponentially rising at an alarming rate and simultaneously causing an increased incidence of substantial adverse effects, and predisposition to various comorbidities such as osteoarthritis, coronary heart disease, and hypertension [1, 2]. Globally, obesity has precipitously grown to become a pandemic in all countries due to several contributing factors from vicissitudes in human lifestyles and societal norms, in addition to the multi-factorial existing causes of obesity: genetics, dietary intake,

and lifestyle modification [3–5]. Putting all these puzzles together, obesity represents a major healthcare crisis, both medically and economically around the globe [6–8].

Identifying and categorizing obese from the non-obese or even from the overweight that is deemed borderline between the non-obese and the obese individuals involve the classification based on Body Mass Index (BMI). Obesity classifications and definitions vary but, by and large, the definition by the World Health Organization (WHO) is commonly employed as the gold standard. It defined obesity as a Body Mass Index (BMI) of 30 kg/m<sup>2</sup> or more, 25–29.9 kg/m<sup>2</sup> as overweight, and 18.5–24.5 kg/m2 as normal BMI while less than 18 are considered underweight [9].

#### **2. Global epidemiology of obesity**

On March 4, 2022, the news release theme by the WHO [10] on "World Obesity Day 2022" was "Accelerating action to stop obesity" but will it ever come about? Well, the answer is feasible! Less likely of course because the world has yet to recognize obesity as a disease or pandemic that is inevitable if strict measures are not taken to control the modifiable risk factors that are most probable factors. As such the WHO is encouraging countries to act more to overturn this foreseeable and escapable health crisis. According to the WHO news release, greater than 1 billion people globally are obese of which 650 million were adults, 340 million were adolescents, and 39 million were children [11]. More astonishing is the fact that this number is still increasing. WHO estimates that by 2025, about 167 million people: adults and children will become less healthy because of being overweight or obese [12]. Between 2011 and 2014, the gross proportion of the prevalence of obesity among adults in the United States was 36.5%, by 2016, the figure rises more, 38.9% of US adults were obese while 7.6% were classified as severely obese [13, 14]. Between 2017 and 2018, 41.9% of women 20 years and more of the US were said to be obese [15]. In 2016, 13% of adult globally were said to be obese [16]. Overall, middle-aged individuals 40–59 years old (40.2%) and older aged individuals 60 and above (37.0%) had a greater incidence of obesity than younger adults aged 20–39 (32.3%) [17]. Overall gender predilection shows that women (38.3%) had a greater propensity for obesity than men (34.3%) [18].

Heightened prevalence of obesity and overweight are being reported in several nooks and crannies of the globe: in the Middle East region, the prevalence of obesity and overweight among people 40 years old and above between 2000 and 2006 was 21.17% but increased to 33.4% between 2014 and 2020 [19]. In Europe, obesity prevalence is estimated at 60% among adults populations [20], approximately even higher than 60% in Asia [2]. According to the [21], over half of the British population were said to be overweight between 1980 and 1995, the prevalence of obesity in Britain also doubled from 8% to 15% in 2016, in fact it was projected that by 2050, 15% and 62% of females in social class I and class V will be obese [22]. Most of South America and parts of Asia reported it at 16.4% from 2015 to 2019 in China [23]. Country-wise according to the world population review, the highest obesity prevalence was recorded in countries such as Nauru 61%, Cook Island 55.9%, Palau 55.3%, Kuwait 37.9%. In the US, obesity prevalence has risen from 19.4% in 1997 to 31.4% in 2017 [24] and 36.20% in 2022 while the least was reported in Japan 4.30%, India 3.90%, Timor Leste 3.80%, Bangladesh 3.60%, and Vietnam 2.10% (full description in **Figure 1**).

Globally, the proportion of obesity is higher in women than in men by approximately 1.6-fold, at least to a certain extent, that a female higher occurrence rate would be anticipated, owing to the biologically higher ratio of body fat in women [25].

In some societies, the rate of obesity is higher in lower socio-economic classes, this can be attributed to the greater degree of fast-food restaurants in low-income districts, the higher price of healthful diets, safety fears that inhibit walking and other outdoor activities, and greater economic woes [26–28].

#### **Figure 1.**

*Illustration of obesity prevalence by countries. (Obesity Rates by Country 2022: https://worldpopulationreview. com/country-rankings/obesity-rates-by-country).*

#### **3. Etiology of obesity**

Not only does obesity affects 15% of the global populace, but it is also an underlying cause for several other chronic diseases, yet, surprisingly, it has until recently been regarded as a disease. The genesis of obesity is multi-factorial likewise the epidemic is almost certainly associated with rising sedentary daily life combined with increased desire for satiety satisfaction. However, this is not always so for every obese individual because there is substantial evidence of genetics: obesity-inherited link in the vast majority of traits.

Obesity in the form of weight gain is a continuous process resulting from the constellation of genetic, behavioral, environmental, physiological, social, and cultural factors that ultimately lead to energy imbalance and accumulation of excessive fat deposits [29, 30]. A heightened desire for taste satisfaction and abundant inexpensive, energy-dense readily available fast food increases energy consumption, because these promote feasting out of home, provides varieties of food options and large portions [31]. These eventually will lead to an imbalance between energy intake and energy output. The identification and understanding of the neuronal substrates mediating overeating (after consumption of a high-energy meal) explain the increased neural activity in the amygdala: the interstitial nucleus of the posterior limb of the anterior commissure (IPAC). The neurons in the IPAC system can be activated and switched on after eating or upon food smelling which eventually increases satiety in eating habits [32]. Being a complex system, the amygdala interface with other limbic structures to regulate emotion, learning, and behavior, through these interactions, it modulates and plays a role in the emotional-eating pattern that eventually promotes the overeating response [33, 34]. However, there are other mechanisms for increasing weight gain and many other mechanisms are still unclear.

Leptin, a neuromodulator protein formed predominantly in the white subcutaneous adipose tissue is a crucial body-weight regulator in the human feeding and satiety cycle [35, 36]. Leptin sends satiety impulses to the hypothalamus and thus decreasing food intake and fat storage while ensuring modulation of energy expenditure and carbohydrate metabolism, and finally averting excessive weight gain [37]. Most of the people living with obesity are not leptin-deficient but, they actually have a leptinresistant condition. Thence, they have higher levels of circulating leptin. Women have higher leptin levels than their male counterparts, and these higher leptin levels have a direct relationship with potentially higher BMI in females.

Among other pathways are Hypertrophic-hypercellular obesity wherein the adipose tissues or fat cells increases in size and number and are manifested as abdominal obesity, commonly noticeable in adulthood [38, 39]. With some of these primary adipocytes-secreting pro-inflammatory products: Tumor necrosis factor–alpha TNF-α, Interleukin 6 IL-6, Monocyte chemoattractant protein–1 (MCP-1), etc. acting as active metabolites that support lipid storage, fatty acid synthesis and lipids exudate from adipocytes deposits [40, 41]. Effect of hormones, neurotransmitters, and neurogenic signals on feeding habits are also worth mentioning. Certain hormones such as endocannabinoids increases appetite, promote nutrient uptake, and promote lipogenesis. There are other varieties of gut hormones such as glucagon-like peptide-1 (GLP-1), neuropeptide YY (PYY), and cholecystokinin that act substantially to induce satiety to affect eating habits [42, 43].

The benefit here is that understanding these pathways also gives science possible therapeutic targets for obesity control. Ultimately, the occurrence or increase of obesity resides in an imbalance between energy intake and energy expenditure over a lengthy period, therefore the etiology can be seen as surplus energy intake relative to daily energy expenditure, or as low energy expenditure relative to daily energy intake.

#### **4. Obesity and other chronic disease pathophysiology**

Obesity-related health conditions are numerous and associated with increased morbidity and greater mortality. The major obesity-related comorbidities include cardiovascular disease (majorly heart disease and stroke), type 2 diabetes, dyslipidemia, musculoskeletal disorders (osteoarthritis especially), and certain cancers (endometrial, breast, and colon) [44]. These illnesses are underlying causes for premature death and substantial health disability. Expert reviews by Chetambath et al. [45] indicated that a BMI of 25–28.9 kg/m2 is associated with a relative risk of 1.72 for coronary heart disease the risk gradually rises with an increasing BMI; for BMIs more than 33 kg/m2 , the relative risk is 3.44. A similar trend was also reported between obesity and stroke respectively [45]. In general, obesity is reported to increase mortality rate from cardiovascular disease by 4-fold and by 2-fold for cancer-related death. Moreso severely obese (BMI ≥40) showed a 6–12-fold probability of an all-cause mortality rate, a reduced life expectancy by 20 years in men, and approximately 5 years in women [46–48]. Although there is no definitive or no cause-and-effect association that undoubtedly established obesity direct cause of these comorbidities, however, improvement of these illnesses after significant weight reduction indicates that high body mass index plays an important role in the propagation of the diseases [49, 50]. A schematic diagram is illustrated in **Figure 2**.

Hypertension (high blood pressure) is among the foremost prevalent comorbidity associated with obesity, and in turn is a crucial risk factor for stroke, myocardial infarction, heart failure, and chronic renal disease [51, 52]. Independent risk factors such as high body mass index and/or overweight are 65–75% linked to primary (essential) hypertension [53], with at least 72% contribution in hypertension and/or T2DM

**Figure 2.**

*Schematic diagram of obesity-related chronic disease.*

diagnosed patients with end-stage renal disease, although the mechanism is yet to be fully understood [53]. Nonetheless, significant progress has been made in explaining some of the intricate relationships between renal, hormonal, and neurological system components that connect excessive adiposity with high blood pressure. Literally, the amount of blood flowing through the body increases with increased body weight, and this place additional pressure on artery walls, leading to increased arterial blood pressure (hypertension). Besides this, being overweight also increases the heart rate and thus makes blood flow within the blood vessel harder. Obesity generally reduces the parasympathetic pitch and intensifies sympathetic activity. These autonomic activity modifications cause increased heart rate, decreases heart rate variability, and reduced baroreflex sensitivity. According to the Nurses' Health Study in the United State, women who had a BMI above 32 had a four times higher mortality rate from cardiovascular disease than those who had a BMI under 19 [54–56].

Pulmonary function is also a prognosticator of various recurring illnesses even though various research outcomes on the obesity-lung function association are inconsistent. Nonetheless, a lot of research have reported central obesity as a reliable indicator of poor lung function [57]. Obesity is a serious mitigating condition that is frequently associated with respiratory problems, thus reducing the exercise-tolerance capacity of the obese perhaps due to early exhaustion. Obesity is the main culprit in obstructive sleep apnea, a condition that disrupts sleep, produces snoring and apneic episodes, and lowers oxygen saturation to levels associated with potentially fatal cardiac rhythms [58]. Due to modifications in respiratory mechanism and bronchospasm produced by gastroesophageal reflux illness, obesity makes respiratory symptoms such as dyspnea worse [59]. Obesity-lung function association by most studies has focused on the association between lung function and central obesity and central obesity indicators, however, the relationship is inversely purported while for some, the association is weak and for others, there is an independent obesity indicatorslung function interaction [59, 60]. Obesity especially central obesity restricts lung compliance function due to diaphragm-reduced movement (expansion-relaxation function) which eventually limits the respiratory functional capacity of the lungs leading to decreased lung function i.e. FVC and FEV1 in people with central obesity than when compared to the normal population [23]. An alternative possible mechanism is a reduction in the functional pulmonary capacity due to increased deposition of adipose tissues in the pulmonary compartment and respiratory-supporting tissues such as in the abdomen and surrounding viscera [61].

Obesity increases the risk of arthritis especially primary osteoarthritis (OA), a degenerative disease that causes excessive matrix degradation on the weight-bearing joints such as the hips, knees, and ankles as well as the possibility of foot discomfort and plantar fasciitis, all of which may lead to secondary limitations in physical activity and further weight gain [62]. Although osteoarthritis etiology is multi-factorial, obesity is labeled as the single most predisposing modifiable factor to OA. Increased weight-bearing condition such as obesity causes changes in the articular joint bony structures (joint space narrowing). There is subchondral ablation of the articular bony-cartilage layer of the joint leading to a greater loss of joint space on the weight-bearing joint [63], the proteoglycans level drops significantly to a critical level that makes the articular cartilage to become soften and lose its elasticity character, thus, further compromising joint surface integrity [64]. The resulting features of osteoarthritis arise i.e., pain, stiffness, and reduced movement because of the inconvenience caused by overloading (obesity). Significant weight loss is linked to a decrease in arthritic joint discomfort, and in some people, it may prevent or delay the need for joint replacement surgery [65].

#### *Obesity: A Prerequisite for Major Chronic Illnesses DOI: http://dx.doi.org/10.5772/intechopen.111935*

Obesity has been reported to have a direct correlation with non-alcoholic fatty liver disease, increased gastric disease and hepatobiliary diseases are also associated with obesity [66]. Because of their increased biliary excretion of cholesterol, obese people are more likely to develop gallstones, cholecystitis, and biliary dyskinesia (biliary colic without cholelithiasis) [67]. Although cholesterol is eliminated and released when lowering fat storage, it may solidify in the gallbladder and raise the risk of cholelithiasis and cholecystitis. Small quantities of fat consumed every day as part of a weight reduction plan may empty the gallbladder and lower this risk. Non-alcoholic fatty liver disease caused by obesity may lead to cirrhosis and liver failure but is often preventable or mitigated by weight loss [68].

There is a strong evidence indicating that obesity is directly associated with cancer, there are prevalence evidence of obesity propensity for certain types of cancer: endometrial cancer is 7-fold and 2–4 times increased in the severely obese and obese/overweight respectively, esophageal adenocarcinoma is about 4–8 fold high in severely obese and 2.4–2.7 times more likely among obese individuals [69, 70], gastric cancer, kidney cancer and liver cancer are 2-fold higher with obesity, for others, its 1.5 fold likely for colorectal cancer,1.6-fold for gallbladder cancer, 1.2–1.4 and 0.8 times for breast postmenopausal and premenopausal cancer respectively, 1.1 times for ovarian cancer, and 1.3 times for liver cancer [69, 70].

Obesity and cancer remain a topic of investigation**.** Being overweight or obese can induce alterations in the body tissues that increases cancer propensity [71]. These alterations comprise long- *there are prevalence evidence of obesity propensity* levels of other hormones, such as insulin, insulin-like growth factor, sex hormones, as well as alteration of adipocytokine levels like leptins, adiponectin, and visfatin [72]. How obesity increase risk of cancer involves several possible mechanisms including: (1) Fat tissue-increase of estrogen and thus heightened risk of cancer of the breast, ovaries, endometrial etc., (2) hyperinsulinemia from elevated free fatty acid levels in the obese that cause insulin resistance and the eventual increased blood glucose that increases the risk hyperinsulinemia, (3) low-grade inflammation and oxidative stress that affect growth-promoting cytokines and immune modulation, and (4) intestinal flora microbiomes alteration [73].

Very astonishing to know that 20% of all cancer cases are thought to be associated with excess weight gain, and obesity [74], although tumors' etiologic routes are driven by several factors and the mechanisms varies with respect to tumor-type. People living with obesity have an approximately 1.5–3.5-fold greater chance of developing certain cancer-types compared with normal-weight people [75], however, this latter statement does not imply that an overweight or obese person will definitely develop cancer, but the chances rise. Being overweight or obese raises the risk of 13 cancer-types namely: cancer of breast in post-menopausal, ovarian, esophageal, thyroid, pancreas, kidney, hepatocyte, stomach, gallbladder, myeloma, and meningioma of the brain [76]. In Europe, more than 1 in 20 cancer incidents are attributed to excessive weight in the UK [77]. Breast cancer risk is lower among those who lose weight, especially postmenopausal women. Less robust data exist for cancer patients, but observations pointing to a long history of poor outcomes for obese women with breast cancer are well detailed [76]. Even though there are different ideas about how obesity affects the outcome of different cancers, there is much evidence that exercise is advantageous for breast and colon cancer [78, 79]. According to a meta-analysis research that was published in 2002, obesity was the root cause of 11% of instances of colon cancer, 9% of cases of postmenopausal breast cancer, 39% of cases of endometrial cancer, 25% of cases of kidney cancer, and 37% of cases of esophageal cancer [80].

Although there are few studies that look at weight or changes in weight with survival after cancer diagnosis but obesity and poor outcomes for breast cancer survivors have long been reported by researchers. The majority of evidence indicates that being overweight/obese at diagnosis is the main lifestyle risk factor for having a poor prognosis for breast cancer and a poor quality of life status [81] thus, supporting the growing evidence demonstrating that gaining weight after diagnosis increases risk [82]. The importance of energy balance after breast cancer is further supported by research showing that physical activity reduces the risk of breast cancer recurrence [83] as intervention trials of diet and exercise showed longer disease-free survival among intervention groups of which lost significant weight than the control group [84].

On the other hand obesity is one of the most significant risk factors for developing stroke [85]. Both genders and several ethnic communities, including Caucasians, Chinese, and Japanese people, have shown a substantial connection between obesity and an elevated risk for ischemic stroke [86]. The American Heart Association and the American Stroke Association advise managing obesity for both primary [87] and secondary stroke prevention [88] in light of such results. The pleiotropic effects that a number of cytokines released by adipose tissue may have on vascular wall, inflammation, and insulin resistance are thought to be a plausible underlying mechanism relating obesity and stroke [89]. Adiponectin and hepatocyte growth factor are two examples of these adipokines, and low levels of adiponectin and high levels of hepatocyte growth factor have both been linked to an increased risk of strokerelated morbidity [90]. Adiponectin levels and the frequency of ischemic stroke, however, were not shown to be significantly correlated in other investigations [91]. Furthermore, in the morbid obese, higher stroke mortality was linked to both low and high adiponectin concentrations probably due to the transgene-mediated overexpression of adiponectin that causes morbid obesity due to decreased energy expenditure [92]. Additionally, according to a recent meta-analysis [93], individuals who were obese or overweight had a relative risk for ischemic stroke of 1.64 (95% CI: 1.36–1.99) and 1.22 (95% CI: 1.05–1.41), respectively, thus showing incrementally increased risk with increased BMI. Multivariate analysis of data from four cohorts involving 76,227 Chinese individuals revealed an increase of 2 kg/m2 in baseline BMI resulting in 6.1% increase in the relative risk of total stroke [94].

#### **5. Assessment of obesity as a comorbidity burden**

Waist circumference is another clinically feasible measurement that may be used independently or in addition to body mass index BMI to assess weight-related health risk. The World Health Organization has identified sex-specific waist circumference values that signify increased health risk (≥80 cm for women, ≥94 cm for men) and substantially increased health risk (≥88 cm for women, ≥102 cm for men) [95, 96]. Waist circumference correlates well with BMI requiring only a tape measure to provides an estimate of abdominal fat. Abdominal fat is more strongly associated with health risk than fat stored in other regions of the body. Globally, the WHO obesity classification based on body mass index is the easily and generally adopted classification. Base on BMI it classifies obesity as >30 kg/m2 for obesity, 25–29.9 kg/m<sup>2</sup> for overweight, 18.5–24.9 kg/m<sup>2</sup> for normal, and < 18.5 kg/m<sup>2</sup> as underweight and further classified obesity into 3 more categories of 30–34.9 kg/m2 for obese-1, 35–39.9 kg/m<sup>2</sup> for obese 2 (super obese), and >40 kg/m<sup>2</sup> for obese 3 (morbid obesity) [97].

*Obesity: A Prerequisite for Major Chronic Illnesses DOI: http://dx.doi.org/10.5772/intechopen.111935*

The World Obesity Federation (WOF) reiterated that obesity is a progressive disease process that can be chronic and relapsing in nature. Like other chronic illnesses, it's a progressive disease process where the diagnosis is based on some specific parameters such as high body mass index (BMI) value, where the higher the BMI, the more likelihood the devastating clinical consequences [22]. For example, patients with a BMI >30 reports more red flag signs such as shortness of breath and other specific disease symptoms concerning cardiopulmonary systems compared to patients within the normal BMI range [17].

#### **6. Problem statement with obesity**

The association between obesity and other life-threatening chronic diseases demands critical scrutiny, as obesity propensity for other diseases is estimated to be about 42% for both overweight and obese [11]. In the West, obesity is one of the most prevailing health problems associated with an increased tendency for development of several medical illnesses and premature loss of life [98], although this trend is fast germinating in the developing world too. Obesity predicaments caused a vast economic setback for medical facilities, and it created a massive financial meltdown for many nations, especially developing countries with poor health insurance and inadequate financial support. Besides, obesity is also linked with a reduced quality of life resulting from a number of associated diseases such as joint degenerative problems that cause pain and restrictions in carrying out daily activities and/or atherosclerosis that leads to Myocardial infarction and heart failure [98]. Obesity affects several portions of our bio-metabolic system from the heart to the liver, kidneys, joints, and reproductive system. It is associated with prevalence of multiple non-communicable diseases, such as type 2 diabetes, cardiovascular disease, hypertension, and stroke, and overall mental health in general. People living with obesity are also three times more likely to be hospitalized for infectious diseases like COVID-19 [99, 100].

At the psychosocial and economic level, obese individuals are less likely to obtain insurance, employment, promotion or enjoy personal relationships due to their quality-of-life predicament and health hindrances or even public stigmatization. Prevention especially and treatment of obesity is therefore now widely and critically recognized as the main priority for most healthcare governing bodies especially the WHO chapter of the United Nations [20]. The myriad of clinical implications of obesity make caring for obese patients a priority for most physicians, especially as mortality rises exponentially with increasing body weight [101, 102].

Psychosocial wellbeing is a measure of health or mental status in the form of quality of life. Although, the latter is a multidimensional notion that evaluates quality of life (QoL) and is associated with rising obesity level globally. QoL is an independent appraisal of both satisfactory and obnoxious features of life because the presumption is that people with higher BMI or weight are more probable to come up with an occurrence of certain mental situations [103]. Physical health in the form of phenotypic changes is a crucial contributing factor to overall quality of life [104]. Clinicians are increasingly coming to terms with the intricate association of obesity with quality of life because obesity is regarded as an important indicator and measure of quality of life. Obesity and psycho-mental disease such as anxiety-depressive disorder have a twisted and communal relationship, this is because obesity enhances the likelihood of getting a psychiatric diagnosis, and that the psycho-mental disorder may in turn further contribute to more weight gain and obesity [105]. Most of the available data

from different research on the relationship between obesity and psychological diseases focused on the major depressive disorder, where the association has been proven to be strong [105]. Although the results of different research vary, the consensus is that there is a correlation between psychopathology and obesity for the majority of common or serious mental illnesses.

Comprehending the societal insights, demands, mindsets, perceptions, and preferences of individuals who are obese is essential because studies revealed societal observation and inclination more often than not have a negative perception towards people living with obesity [106, 107]. Often deem pessimistic due to low self-esteem and discrimination, body discrediting, and stigmatization. This could culminate in several adverse outcomes ranging from depression, anxiety, social phobia, declining medical support, and largely poor quality of life [106, 108]. These implanted unconstructive notions and trials encountered significantly derail or suppress their enthusiasm to manage their life situations thus, leading to a lack of devotion to weight-managing programs: lifestyle modifications, and pharmacological therapies. A detailed comprehension of the perceptions, attitudes, and preferences of the obese individuals is imperative to achieving an encouraging and societal-friendly atmosphere for the well-being of the people living with obesity.

People living with obesity are usually not satisfied with the outcomes from their healthcare provider visits especially if they feel that they were not given sufficient support from friends, or family members needed by them to achieve successful weight-reduction goals [109]. In fact, a study by Agüera et al. [110] showed that most people living with obesity feel that their physicians only accorded them limited time and do not view their health concerns from their own perspectives. These physicians are also reluctant to prescribe weight-lowering medications, they are over-aggressive in promoting strict lifestyle modification advice as the only ultimate way out. Painting pictures of them being at increased folds of developing life complications and poor quality of life.

#### **7. Lifestyle-modifications, exercise and weight control inobesity**

Early recognition and reduction of therapy barriers can conserve resources and increase the likelihood of long-term accomplishment, thereby safeguarding the patient from the medical illnesses and psychosocial, emotional and debilitative aftermath effects of excessive overweight/weight gain. Exercise is a crucial part of the behavioral therapy of obesity, along with dietary and lifestyle modifications. The components of these three therapeutic lifestyle changes or adjustment are essential initial stages in the prevention and treatment, but they are often omitted because of the complexity of their practical application [111]. Healthcare professionals that operate in an integrated team environment with a long-term horizon perspective are best able to deliver exercise along with calorie reduction, lifestyle modification, and in certain circumstances, weight loss medication and surgery, where clinical exercise physiologist play a significant role in this team [112]. The inclusion of clinical exercise physiologists in this type of programming is expected to continue to be successful considering that the prevalence of obesity in the United States and throughout the globe is not expected to decline noticeably in the near future [104]. This strategy makes it reasonable to manage, or perhaps eliminate the comorbidities associated with obesity while reducing the personal burden of obesity in a cost- and careeffective way..

#### *Obesity: A Prerequisite for Major Chronic Illnesses DOI: http://dx.doi.org/10.5772/intechopen.111935*

As increase weight is associated with several factors from excessive food-intake to lack or inadequate daily mobile activity plus environmental and genetic factors, weight reduction and weight maintenance is undoubtedly a major task for individuals living with obesity. Both those with normal weights and those who are obese may benefit from increased physical exercise to improve their cardiovascular health status [113]. Regular bouts of aerobic exercise have been shown to lower blood pressure [114, 115], and visceral fat [114], the latter of which is linked to increased glucose tolerance and insulin sensitivity (in non-diabetic people) and glycaemic control (in type 2 diabetes patients). In another published study [116], investigators looked at 16 twin pairs with different levels of physical activity, they observed that sedentary twins had more visceral, hepatic, and intramuscular high-risk fat. The pairs with more physical activities had improved body composition and adequate metabolic parameters. Exercising 200 or more minutes per week was shown to more comparably weight loss than those who exercising less than 80 minutes per week in obese [117], such similar outcome was revealed in systematic reviews and meta-analyses published between 2010 and December 2019 [65].

In overall, a key to lessening overweight/obesity is early intervention, best even before conception. Balance and nutritious dietary intake in pregnancy, accompanied by exclusive breastfeeding for 6 months and beyond, perhaps until 2 years benefits all infant unobjectionably [118].

Therefore, public health approach to curtail overweight/obesity are crucial, but the evidence that even a modest weight loss is valuable if it is sustained makes management of obesity worthwhile and of paramount importance. A main mitigating factor to successful weight control therapy is time inadequacy, a commonly confronted barriers to obesity control [119]. Concerned individuals usually find it hard to create adequate time and space to take part in physical activity or to adopt healthy dietary routine or pattern. Because overweight/obesity being important global public health challenges, western and developing nations consider obesity as a chronic and progressive disease which demands resources and efforts as with other chronic illnesses and require lifelong management [120]. As such, there is no "quick fix" for overweight/ obesity dilemma. Weight loss programs require great deal of lifelong commitment of dedicated lifestyle adjustment to achieve best weight reduction outcome, with tips on medical support and advice on how best to achieve and maintain a successful weight loss being offered by the medical experts and clinicians.

#### **8. Conclusion**

Consistently keeping an eye on one's BMI level, establishing a practical goal and engaging families and friends in the management routine and fight to lose weight are positive therapeutic steps, this is because, even losing what appears to be a modest quantity of weight, such as 3% or more of one's initial body weight and sustaining it for life-long, can significantly reduce the risk of obesity-related complications such as diabetes mellitus, osteoarthritis and cardiac diseases. If overweight/obesity is left unchecked, there is an increased risk of lifetime illnesses and disability by several folds. Additionally, overweight/obesity among the middle age is linked with poor index of quality of life and more detrimental effects in the older age group. Lastly, gender-wise, the overweight/obese women are more likely to develop depressive episodes and eating disorders, particularly the binge-eating disorder otherwise refer to as bulimia, especially if such individuals requires professional aid with their weight reduction plan. For these challenges and obstacles to weight reduction therapy or plan to be curtailed, appraisal and treatment are very crucial for successful reducing weight and eventual obesity-related chronic diseases.

#### **9. Recommendation**

Altogether, all nations must collaborate in global efforts to establish a better and healthy food ecosystem to avail everybody access to healthy diet. Pro-active measures restricting and regulating the sales of food and drinks high in fats food and drinks to children including introduction of appropriate taxing of sugary drinks. Government should provide cities and towns secured space or tarmac for safe exercising and recreation activities. Healthy diet and lifestyle practices should be taught as courses in schools to educate the pupils as well as public adverts to help families educate their children about a healthy habit. The global governing body that oversees the general wellbeing and world obesity crisis for humanity, the WHO, should intensify its supervision of the nationwide trends on overweigh/obesity prevalence, as well as creation of standard guidelines to tackling the prevention and treatment of overweight/obesity for all nations.

#### **10. Limitation**

The article does not touch on the heterogeneity of the several functions carried out by the neuronal network formed with other brain sections as there is a crucial links between the energy intake and expenditure effects mediated by distinctive neuronal subgroups as portrayed in distinctive brain waves monitoring.

### **Author details**

Hafeez Abiola Afolabi1 , Zaidi Zakaria1 \*, Salzihan Md. Salleh2,3, Ewe Seng Ch'ng4 , Siti Norasikin Mohd Nafi3 , Ahmad Aizat Bin Abdul Aziz5 , Sameer Badri Al-Mhanna6 , Ahmad Adebayo Irekeola7 , Yusuf Wada7 and Abubakar Bishir Daku8

1 Department of General Surgery, School of Medical Sciences, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

2 Department of Pathology, School of Medical Sciences, Hospital Universiti Sains Malaysia, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

3 Department of Pathology, School of Medical Sciences, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

4 Advanced Medical and Dental Institute, Universiti Sains Malaysia USM, Kepala Batas, Penang, Malaysia

5 Department of Human Genome Centre, School of Medical Sciences, Health Campus, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

6 Department of Physiology and Exercise, School of Medical Sciences, Health Campus, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

7 Department of Medical Microbiology and Parasitology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

8 Department of Human Physiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia USM, Kubang Kerian, Kelantan, Malaysia

\*Address all correspondence to: doczakaria44@gmail.com

© 2023 The Author(s). Licensee IntechOpen. 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.

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Section 3
