The Multiple Consequences of Obesity

Abstract

Increase in body weight due to excess accumulation of fat can lead to obesity, a chronic, progressive, relapsing, multifactorial, neurobehavioral disease caused by adipose tissue dysfunction. Obesity often results in adverse biomechanical, metabolic, psychosocial, and economic consequences. In humans, effects of obesity are diverse and interrelated and can be classified on the basis of organ/organ system affected. Physical problems associated with weight gain are musculoskeletal problems, respiratory problems, lower limb venous diseases, skin-related problems, and stress incontinence in females. Metabolic conditions caused by obesity include gout, insulin resistance and metabolic syndrome, type 2 diabetes mellitus, certain cancers, CVD, fatty liver, gall bladder disease, etc. Obesity is known to affect the reproductive health. Hypogonadism and pseudo-gynecomastia are more common in males with obesity. Decreased fertility is reported in both the sexes. Polycystic ovarian syndrome (PCOS), anovulation, endometrial hyperplasia, and increased risk of complications in pregnancy have been reported in females. Persons with obesity have increased healthcare expense, pay more insurance premium, take more illness-related leaves, thus suffering economic loss due to their condition. Persons with obesity are often considered legitimate targets for teasing and bullying, which may cause social isolation, depression, eating disorders, etc. Obesity affects the morbidity and mortality. This chapter deals with the different consequences of obesity.

1. Introduction

Living organisms are constitutionally wired to store energy for survival in periods of scarcity. Eel and salmon are reported to survive long periods without food [1, 2, 3]. The excess intake of calories leads to energy accumulation in the form of fat, glycogen, or starch. Plants store energy reserves as starch and oil. We were unable to find reports of adverse consequences of excess energy storage in plants and lower organisms. The stored energy helps the organism to tide over periods of calorie scarcity and during hibernation, aestivation, or migration in animals. In higher organisms, deposition of excess calories results in impairment of body functions with adverse effects on health and longevity. Obesity with adverse health effects has been reported in zebrafish [4], reptiles [5, 6], and birds [7].

Energy in humans is stored as glycogen or triacylglycerols (TAGs). Relative to the amount of calories that can be stored as triacylglycerols (TAGs), only a small amount of calories can be stored as glycogen. An adult liver can store up to 120 g glycogen, while the skeletal muscles can store up to 400 g glycogen. Triacylglycerols are hydrophobic energy-dense molecules that can be stored in large amounts in the adipocytes. Adipose tissue is the loose collection of adipocytes in a mesh of collagen fibers, deposited at various sites in the body. Preadipocytes, fibroblasts, vascular endothelial cells, adipose tissue macrophages, and small blood vessels are also present in the adipose tissue.

Increased mass of adipose tissue, abnormal site of deposition, or abnormal size of adipocytes can result in adverse consequences on health and quality of life (Table 1).

Type of problems	Examples of associated conditions
Physical problems	1. Musculoskeletal disorders; Decreased mobility Loss of balance Osteoarthritis Gout
	2. Respiratory problems; Decreased lung compliance Increased risk of asthma Sleep apnea
	3. Lower limb venous disease; Thrombosis Varicose veins Venous insufficiency
	4. Skin-related problems
	5. Stress incontinence in females
Metabolic disorders	1. Hyperglycemia
	2. Dyslipidemia
	3. Gout; Hyperglycemia increases risk of skin infections, eye diseases, and kidney diseases.; Both hyperglycemia and dyslipidemia cause insulin resistances, leading to increased risk of type 2 diabetes, cardiovascular disease, stroke, and cancers.
Gut-associated diseases	1. Cholelithiasis
	2. Pancreatitis
	3. Fatty liver
	4. Gastroesophageal reflux disease
Reproductive Health Issues	A. Males; 1. Hypogonadism
	2. Gynecomastia
	3. Decreased fertility
	B. Females
	1. Polycystic Ovarian Syndrome (PCOS)
	2. Anovulation
	3. Endometrial hyperplasia
	C. Increased risk of complications in pregnancy
	1. Gestational diabetes
	2. Preeclampsia
	3. Cesarian section
Economic issues	1. Increased expense on obesity-related diseases
	2. Decreased pay
	3. Decreased job opportunity
Mental and social issues	1. Social stigma
	2. Bullying
	3. Binge eating
	4. Depression
Quality of life and mortality	1. Increased risk of morbidity, mortality decreased quality of life

Table 1.

Multiple consequences of obesity.

2. Physical problems associated with obesity

These result from the abnormally high weight of the affected person and are closely related to each other and to the other consequences of obesity including metabolic dysfunction and insulin resistance. For convenience, we have classified them into musculoskeletal disorders, skin-related problems, respiratory problems, lower-limb venous diseases, and urinary incontinence.

2.1 Musculoskeletal disorders

These include decreased mobility, loss of balance, and osteoarthritis, which are associated with abnormal increase in body weight (Figure 1).

Figure 1.

Association of obesity with musculoskeletal disorders.

2.1.1 Decreased functional mobility

Obesity is one of the major causes for the loss of functional mobility. Altered posture and gait resulting from abnormal fat deposition, compromised bone strength, pain, and breathlessness compromise the mobility [8], which must be taken into account by treating physicians advising increased physical activity for weight loss. Decreased mobility results in further increase in weight.

2.1.2 Loss of balance

Increased weight, decreased mobility, and altered posture result in loss of balance, increasing the risk of falls and injury [9]. In spite of the cushioning effect of the fat mass, falls in patients with obesity are more serious and require higher treatment costs and specialized care [10].

2.1.3 Osteoarthritis (OA)

Progressive loss of articular cartilage and formation of osteophytes (bony spurs usually caused by local inflammation) result in osteoarthritis [11]. Obesity is a risk factor for OA of knee, hands, and wrist (but not of hip) [12]; thus excessive body weight alone cannot fully explain the increased incidence of OA in people with obesity. Increased body mass index (BMI) in obesity results in altered gait and increased strain on the knee, causing biomechanical joint loading [13]. This is associated with increased expression of matrix metalloproteinases in chondrocytes and increased degradation of proteoglycans [14]. Synthesis of DNA, proteoglycans, and collagen is decreased, contributing to the loss of cartilage in joints [14]. Chondrocytes subjected to high loading show increased expression of pro-inflammatory cytokines including TNF-α and IL-1(β), along with an increased expression of cyclooxygenase-2 leading to increased PGE2 (responsible for inflammatory pain) synthesis [15].

Increase in the amount of adipose tissue leads to metabolic dysfunction: obesity-related sarcopenia, deposition of intramuscular lipid, and chronic low-grade systemic inflammation, all of which contribute to osteoarthritis [16].

2.1.4 Gout

Insulin resistance, often seen in patients with obesity, causes decreased excretion of uric acid, leading to hyperuricemia [17, 18]. Adipose tissue is known to express all the components of renin-angiotensin system (RAS), including angiotensinogen [19]. The resulting hypertension may cause glomerular arteriolar damage and reduce uric acid excretion. Hyperuricemia and gout have been associated with osteoarthritis [20, 21].

2.2 Respiratory problems

Obesity is associated with various respiratory problems that are correlated with each other (Figure 2).

Figure 2.

Association of obesity with respiratory disorders.

2.2.1 Reduced compliance of lungs

Increased fat deposition in the mediastinum and abdominal cavity increases intra-abdominal and pleural pressure, thus reducing compliance of the lungs. Altered breathing pattern, with decrease in expiratory reserve volume (ERV), functional reserve capacity (FRC), and tidal volume (TV), with slight increase in mean respiratory rate have been reported in subjects with obesity [22, 23], Obesity has little effect on the residual volume (RV) and total lung capacity (TLC) [24].

2.2.2 Obesity and asthma

The relationship between obesity and asthma has been established by a meta-analysis involving more than 300,000 adults [25]. The expression of adipokines secreted by adipose tissue is different in persons with obesity. Decreased expression of adiponectin (anti-inflammatory adipokine) and increased expression of leptin (pro-inflammatory adipokine) have been reported in asthmatic patients with obesity [26]. Leptin, an anorexigenic hormone, increases metabolic rate and is involved in surfactant production and neonatal lung development [27]. Sood et al. [28] have reported a strong association between high BMI and high levels of serum leptin with asthma in adults.

Inflammatory cytokines such as TNF-α, IL-8, and monocyte chemoattractant protein-1 (MCP-1) have also been reported to be raised in persons with obesity. However, their role in asthma associated with obesity is not clear [29]. In older patients, abdominal obesity and metabolic syndrome have been reported to be associated with restrictive lung disease [30].

2.2.3 Obstructive sleep apnea (OSA)

The prevalence of obstructive sleep apnea in adult persons with obesity is about 45%, compared with 25% in persons with normal weight [31]. Increased fat deposit in tissues surrounding the upper airway decreases the size of lumen and increases collapsibility of the upper airway. OSA may cause sleep fragmentation, which may lead to sleep deprivation [32]. Since experimental sleep deprivation and self-reported short sleep have been linked with metabolic dysregulation, it is possible that OSA may also be a contributing factor in metabolic dysregulation associated with obesity.

2.3 Lower limb venous diseases

Venous diseases (blood clots, deep vein thrombosis, superficial venous thrombosis or phlebitis, chronic venous insufficiency or CVI, varicose and spider veins, and venous stasis ulcers) may be caused by one or more of the following factors: immobility (as in bed-ridden patients) leading to stagnation of blood), blood vessel injury caused by trauma/needles/intravenous catheters/infections, central venous hypertension, conditions that increase the blood coagulation, and pregnancy. Different cancers are associated with deep vein thrombosis.

Varicose veins and chronic venous insufficiency are more common in aged women compared with men. Obesity has been found to be associated with all types of lower limb venous diseases (Figure 3). Willenberg et al. [33] showed that lower limb venous flow parameters are different in healthy persons with and without obesity. Various epidemiological studies show that obesity is associated with chronic venous disease, phlebitis, and thromboembolism [34, 35, 36, 37]. Untreated CVI results in increased pressure and swelling leading to rupture of capillaries. The skin may appear reddish-brown and becomes sensitive to bumps and scratches. Burst capillaries may lead to inflammation and even ulcers.

Figure 3.

Obesity as a cause of lower limb venous diseases.

Increased intra-abdominal pressure caused by central obesity is transmitted to the extremities via femoral veins leading to resistance to venous return, producing venous valvular insufficiency. The self-perpetuating cycle of worsening venous insufficiency causes venous stasis and distension of veins in the lower limb. Obesity produces a chronic low-grade inflammation, which damages the affected veins and increases the risk of thromboembolism [33].

2.4 Skin problems

Different problems of the integumentary system associated with obesity can be classified on the basis of their pathophysiologic origin (Figure 4). Skin lesions associated with mechanical causes include striae, lipodystrophy, plantar hyperkeratosis, and venous insufficiency. Acanthosis nigricans and skin tags or acrochordons are due to insulin resistance. Obesity-related hyperandrogenism may cause acne, hirsutism, and androgenic alopecia. Skin folds created by obesity increase the risk of intertrigo and infections.

Figure 4.

Dermatological manifestations associated with obesity.

2.4.1 Mechanical causes of dermatologic manifestations associated with obesity

Striae or stretch marks are a type of scarring of the dermis associated with stretching of the dermis. Striae distensae may appear as a consequence of pregnancy, puberty, or obesity and appear on abdomen, breasts (in females), and shoulders (in body builders). They are more common in females. [38]. Striae atrophicans due to thinning of the skin may appear in adrenal gland disorders [39].

Other dermatological conditions with mechanical causes include intertrigo, conditions associated with chronic venous insufficiency, and lymphedema [40]. Intertrigo is an inflammation of skin resulting from friction between opposing skin surfaces of skin folds. It may have an infectious component. Axilla, groin, intergluteal, and inframammary areas may be involved [41]. Hot, humid climates and obesity (BMI > 30 kg/m²) are known to promote intertrigo. Persons with obesity tend to sweat more.

Dermatologic sequelae of chronic venous insufficiency (discussed above) are often seen in patients with obesity and include pitting edema, varicose veins, telangiectasia, hyperpigmentation, venous stasis ulcers, and scaling of the skin (stasis dermatitis) [42].

Blocking or damage of the lymphatic system resulting in accumulation of lymph in soft tissues, especially legs or arms, is called lymphedema. Obesity is a risk factor for secondary lymphedema [40].

2.4.2 Obesity-related endocrine disorders of skin

These include skin tags, acanthosis nigricans, keratosis pilaris, hidradenitis suppurativa and hirsutism, and plantar hyperkeratosis.

1. Skin tags or acrochordons. Skin tags are soft cutaneous growths, usually benign, more commonly seen in persons with obesity, metabolic syndrome, type 2 diabetes, or in persons with family history of skin tags [43]. They occur in both males and females, usually later on in life, but are less common after the seventh decade. The polypoid lesions are skin-colored, brown, or red, 1–5 mm in size (rarely larger) with a loose edematous fibrovascular core, and may be attached to a fleshy stalk. They are more common in skin folds: axilla, groin, eyelids, and neck [44]. Although not painful, they can cause trouble by getting caught in clothing or jewelry, resulting in itching or bleeding. However, skin tags in large numbers may be seen in patients with Birt-Hogg-Dube (BHD) syndrome and tuberous sclerosis, where they appear around the neck: the molluscum pendulum necklace sign [45, 46].

2. Acanthosis nigricans (AN). Hyperpigmented velvety plaques usually in body folds, neck, knuckles, and scalp may be seen in patients with obesity. The condition was first reported more than an hundred years ago in the Atlas for Rare Skin Diseases. The term acanthosis nigricans was proposed by Paul Gerson Unna and published in 1891 in a case report by Sigmund Pollitzer [47]. Obesity-associated AN was previously called pseudo acanthosis nigricans; however, this term is incorrect. This is because the initial cases identified in Europe were associated with abdominal or pelvic malignancies. Association of AN with obesity was first reported by Robertson and Tasker in 1947 [48]. Like acrochordons, AN is also associated with insulin resistance often seen in obesity. Probably, the hyperinsulinemia seen in insulin resistance leads to direct and indirect activation of the insulin-like growth factor receptor, triggering proliferation of the dermal fibroblast and epidermal keratinocyte [49]. Friction and perspiration may also be involved in the development of AN [50].

3. Keratosis pilaris (chicken skin) is a benign condition of the skin in which sterile papules occur on the skin (collections of dead skin cells). Though these papules may occur anywhere on the body (except palms and soles), they are more common on the posterior aspect of upper arms, anterior aspects of thighs, face, and buttocks [51].

4. Hidradenitis suppurativa or acne inversa is a chronic painful condition of the terminal follicular epithelium in the apocrine gland–bearing skin (groin, bottom, axilla, breasts) [51]. It affects about 1% of the population and is strongly associated with smoking and obesity. It is also linked with hyperandrogenemia, as many patients have acne and hirsutism [52].

5. Hirsutism, acne vulgaris, and androgenic alopecia seen in some female patients with obesity (with or without polycystic ovarian syndrome, PCOS) are due to hyperandrogenemia, often associated with peripubertal obesity [51, 52, 53, 54]. Increased insulin production (hyperinsulinemia) due to insulin resistance in obesity increases IGF-1 levels and augments ovarian androgen production [55]. Hyperinsulinemia produces a decrease in serum level of steroid hormone binding globulin (SHBG), resulting in a further increase in the level of free testosterone. Treatments that reduce insulin levels usually correct hyperandrogenemia and ovulatory dysfunction [56].

6. Plantar hyperkeratosis (thickening of skin over metatarsophalangeal joints, caused due to increased pressure and mechanical stress placed on the feet) is seen in almost 50% patients with obesity [40]. Increased circulating levels of IGF-1 seen in hyperinsulinemia lead to overactivation of IGF-1 receptors on fibroblasts and keratinocytes. The abnormal IGF-1 signaling causes cellular hyperproliferation (Figure 4).

2.4.3 Increased risk of skin infections

Obesity has been associated with an increased risk of skin, respiratory tract, and urinary tract infections [57]. An increased risk of community-acquired infections has been reported by Harpsoe et al. [58] in both overweight and underweight women. Obesity alters the function of skin, sebum, and sweat glands, affects the structure of collagen and subcutaneous fat, and slows wound healing. A number of skin infections that are more common in persons with obesity include candidiasis, candida folliculitis, furunculosis, tinea cruris, and folliculitis. Cellulitis is less common [42].

2.4.4 Obesity-associated immune disorders affecting skin

Normal adipose tissue in a nonobese person has a population of anti-inflammatory/regulatory immune cells: M2-macrophages and regulatory T cells. These are replaced by pro-inflammatory cells: M1 macrophages, Th1, Th17, and cytotoxic T cells in adipose tissue in persons with obesity [59]. Systemic immune adaptations in obesity include increased number of circulating monocytes, neutrophils, Th1, Th17, and Th22 cells. The pro-inflammatory cytokines produced by pathogenic adipose tissue (IL-1β, IL-6, IL-17, and IFN-γ) result in a chronic low-grade inflammation. Skin conditions such as psoriasis, atopic dermatitis, and eczema are strongly associated with obesity [60]. Hashba et al. [61] have suggested the association of lichen planus with obesity.

2.5 Urinary incontinence (UI)

Urinary incontinence may be of different types: stress incontinence when pregnancy, childbirth, etc., weaken the muscles supporting and controlling bladder; urge incontinence caused by involuntary action of bladder muscles; and mixed incontinence that shares the causes of both stress and urge incontinence. Thyroid problems, uncontrolled diabetes, and medicines such as diuretics can worsen the problem of UI. High BMI, especially BMI higher than 40 kg/m², has been strongly associated with stress predominant incontinence including mixed incontinence [62]. Central obesity increases the abdominal pressure, which increases the bladder pressure and urethral mobility, leading to UI. Chronic strain and stretching seen in pregnancy and abdominal obesity weaken the muscles and other structures of the pelvic floor. Surgical and non-surgical weight loss has been reported to decrease incontinence and improved quality of life.

3. Metabolic disorders associated with obesity

3.1 Organization of the adipose tissue

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

Based on the metabolic features of the adipocytes, adipose tissue (AT) can be white adipose tissue (WAT), which stores excess energy as fat, and brown adipose tissue (BAT), which dissipates stored energy as heat (Figure 5). Both WAT and BAT are present in mammals and are formed throughout life. In humans, WAT development begins during early to mid-gestation period. WAT adipocytes contain a large single (unilocular) droplet of triacylglycerols occupying 90% of the cell volume, with the cytoplasm and the nucleus squeezed to the periphery. Adipocytes of BAT are smaller, multilocular, and contain mitochondria and uncoupling protein-1 (UCP-1), which is involved in non-shivering thermogenesis. The brown appearance of BAT is due to high vasculature and high mitochondrial content. It has a high density of noradrenergic parenchymal fibers. BAT is 5–10 times more vascularized than WAT. A third type of adipose tissue, the beige or brite (brown in white) adipose tissue with paucilocular adipocytes is dispersed in the WAT [64, 65, 66]. Browning of WAT has been suggested under the influence of the hormone irisin, which is produced by the skeletal muscle during exercise [67]. Adipocytes of WAT and beige adipose tissue are predominantly derived from the Myf 5 negative progenitor cells, while adipocytes of BAT are predominantly from Myf 5 positive progenitor cells. Myf 5 or myogenic factor 5 is a gene for transcriptional factor expressed during embryonic myogenesis [68]. Brown and beige AT show anatomical decline with aging and protect from obesity and type 2 diabetes mellitus (T2DM).

Figure 5.

Types of adipose tissue.

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

3.2 Specialized adipose tissue

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

3.3 Diseases associated with adipose tissue

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

3.3.1 Development of insulin resistance

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

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

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

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

Recent evidence suggests the role of leptin resistance and hyperleptinemia of obesity causes production of reactive oxygen species (ROS) and increases oxidative stress, promoting the risk of hypertension, heart disease, and cancer [84, 85, 86]. Endoplasmic reticulum stress, protein tyrosine phosphatase 1B, and suppressor of cytokine 3 (SOC3) signaling mediate leptin resistance and are also involved in insulin resistance [87].

3.3.2 Type 2 diabetes

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

3.3.3 Fatty liver

Hepatic insulin resistance caused by DAG and ceramide promotes lipotoxicity, ectopic fat deposition, insulin resistance, and steatosis, leading to nonalcoholic fatty liver disease (NAFLD) [89].

3.3.4 Obesity and cardiovascular disease

Excess free fatty acids reaching the heart can be stored as epicardial adipose tissue (EAT), also called pericardial fat (present between the visceral and parietal pericardia), or surrounding the blood vessels (perivascular adipose tissue or PVAT). Although the cardiac muscle uses free fatty acids for obtaining energy, when delivered in excess these fatty acids are stored as ectopic fat in the cardiac myocyte, disrupting its function. Higher levels of LDL and VLDL receptors are expressed in the epicardial tissue from patients with T2DM. The PVAT produces adipokines and many molecules that affect vascular reactivity: monocyte chemotactic protein-1 (MCP-1)], nitric oxide, prostacyclin, and angiotensin II. PVAT present around the thoracic aorta resembles BAT, while the PVAT around the abdominal aorta resembles WAT [90, 91]. Healthy PVAT is largely anti-inflammatory, while dysfunctional PVAT promotes atherosclerosis.

3.3.5 Obesity and cancer

Different types of cancers associated with obesity include breast, endometrial, prostrate, pancreatic, adenocarcinoma of esophagus, colon cancer, meningioma, and cancers of ovary, kidney, thyroid, liver, etc. [92, 93, 94]. Though different mechanisms have been proposed, chronic inflammation is a major factor for cancer initiation and progression. Excess nutrients activate metabolic signaling pathways such as c-Jun N-terminal kinase (JNK), nuclear factor κ B (NFκB), and protein kinase R that may promote development of neoplasm [95, 96]. Synthesis of IGF-1 is stimulated by insulin. IGF-1 promotes tumor growth via the PI3K/Akt/mTOR and the Ras/Raf/MAPK pathways [96]. IL-6, a pro-inflammatory cytokine produced during adipose tissue inflammation, activates the androgen receptor and promotes cell survival and proliferation in prostate cancer [97]. Aromatase, the rate-limiting enzyme of estrogen synthesis, is also stimulated by inflammatory cytokines and PGE2 [98, 99, 100, 101].

Risk of gallstones is increased in obesity. Chronic gall bladder inflammation from gallstones may predispose to cancer of the gall bladder [102]. Similarly, chronic inflammation of hepatitis may increase the risk of liver cancer [103].

Cancer survivorship, including cancer progression, prognosis, recurrence, and quality of life are reported to be worsened by obesity [104, 105]. Obesity is associated with an increased risk of treatment-related lymphedema in breast cancer survivors and incontinence in prostate cancer survivors (treated with radial prostatectomy) [106, 107]. Risk of local recurrence was higher in obese/overweight male patients with stage II or stage III renal cancer [108]. Similarly, obesity increases the risk of mortality in patients with multiple myeloma [109].

3.3.6 Eye diseases associated with obesity

Ocular manifestations of obesity are less known and not well documented. Its association with age-related cataract, glaucoma, age-related maculopathy, and diabetic retinopathy has been reported [110, 111]. Cortical and posterior subcapsular or PSC cataracts have been most consistently associated with obesity. Obesity-induced leptin resistance and hyperlipidemia promote formation of reactive oxygen species, which are involved in cataract formation. Other complications of obesity: insulin resistance, hyperglycemia, diabetes, diabetes, and hypertension (see above) are known to be risk factors for cataract.

Increased retroorbital adipose tissue seen in obesity has been reported to be associated with increased intraocular pressure (IOP) [112, 113]. Raised IOP may be a risk factor for glaucoma. The AREDS (Age-Related Eye Disease Study) Report [114] has reported an association between obesity and age-related macular degeneration. (AMD) Oxidative stress secondary to hyperleptinemia may cause damage to lipids in Bruch membrane and secretion of excessive vascular endothelial growth factor (VEGF), which elicit invasion of neovascularization in Bruch membrane in neovascular AMD [115]. Inflammation may also play a role in AMD development. Diabetic retinopathy, a common complication of T2DM (which is associated with diabetes), can result in loss of vision [116]. Other diseases of the eye that may be associated with obesity include retinal vein occlusion, oculomotor nerve palsy, recurrent lower eyelid entropion, keratoconus, papilledema, floppy eyelid syndrome and benign intracranial hypertension (pseudotumor cerebri) [117, 118, 119, 120, 121].

4. Gut-associated diseases

Besides fatty liver and pancreatitis (discussed above), obesity is associated with increased risk of cholelithiasis (gall bladder stones) and gastroesophageal reflux disease (GERD).

4.1 Cholelithiasis

About 90% gallstones are cholesterol stones while the rest are made of calcium bilirubinate, calcium complexes, mucin glycoproteins, or unconjugated bilirubin. Obesity and metabolic syndrome are two risk factors for the development of cholelithiasis, other factors being genetics, age, gender, parity, and presence of hepatitis C virus infection and chronic kidney disease [122]. Recent study by Su et al. [123] shows that obesity reduces the age of onset of gallstone formation. Energy-dense food such as increased consumption of refined carbohydrates and saturated fats with decreased intake of fiber, and medicines such as estrogen and progesterone can promote cholelithiasis [124]. Rapid weight loss of more than 1.5 kg/week can also promote gallstone formation [125].

4.2 Gastroesophageal reflux disease (GERD)

Heartburn and regurgitation are typical manifestations of GERD. Epidemiologic data show an association of obesity with GERD and Barrett’s esophagus, a condition in which the lower part of the esophagus is damaged by repeated exposure to stomach acid [126, 127].

5. Effect of obesity on reproductive health

Obesity has been shown to cause sub-fecundity and infertility in both sexes [128, 129, 130]. Overweight and obesity result in changes in the hypothalamus-pituitary-gonadal (HPG) axis in both men and women, affecting hormone levels and gametogenesis.

5.1 Reproductive problems in males

Chronic inflammation along with insulin and leptin resistance is associated with increase in adipose tissue (see above), affecting reproductive issues.

5.1.1 Hypogonadism and pseudo-gynecomastia

Insulin resistance may be responsible for obesity-induced hypogonadism in males. Male obesity secondary hypogonadism or MOSH is caused by hyperestrogenism, metabolic endotoxemia, and hyperleptinemia. Hyperestrogenism decreases pituitary secretion of luteinizing hormone through a negative feedback action that impairs the synthesis and production of testosterone from Leydig cells. Hypercaloric diet with excess lipids causes breakdown of the normal leaky gut, facilitating passage of bacterial endotoxin from gut lumen into the blood stream (metabolic endotoxemia). Some animal studies suggest that bacterial endotoxin (Lipopolysaccharides-LPS) reduces testicular function by binding toll-like receptor 4 (TLR4) on Leydig cells, stimulating production of inflammatory cytokines [131, 132, 133, 134].

Obesity is associated with elevated levels of leptin and leptin resistance. Leptin prevents the neuropeptide Y (NPY) neurons from inhibiting the release of GnRH. Leptin resistance results in reduced release of GnRH, FSH, and LH and impairs spermatogenesis [135].

Kisspeptin, a hypothalamic peptide encoded by the KiSS1 gene, is an important neuromodulator involved in HPG axis and fertility control. Most kisspeptin cells are localized at the hypothalamic level in humans. Kisspeptin and its G-protein-coupled receptor (KISS 1R or GPR-54) increase the delivery of GnRH into portal circulation, resulting in enhanced secretion of LH and FSH from the anterior pituitary. Decreased endogenous kisspeptin secretion is seen in obesity-related hypogonadotropic hypogonadism (HH) [136, 137, 138, 139]. Increased leptin levels are associated with decreased total and free testosterone levels in males.

Hyperinsulinemia results in decreased production of sex hormone binding globulin (SHBG) by the hepatocytes, causing increased availability of free testosterone for reaction by aromatase in the adipose tissue. Aromatase converts testosterone to estradiol [140], further decreasing testosterone level with increase in estrogen level. This may result in pseudo-gynecomastia, with excess adipose deposition in breast area [134]. Sleep apnea associated with obesity disrupts the nocturnal rise in testosterone [134].

High waist circumference is associated with erectile dysfunction due to atherogenic effect on peripheral vasculature [141]. Low ejaculatory volume and oligo-zoospermia have been noted in males with increased BMI and waist circumference [142]. Increased testicular heat, elevated inflammatory mediators, and increased presence of reactive oxygen species in men with obesity affect the quality of sperms [143].

5.2 Reproductive problems in females

Earlier onset of menarche has been reported in adolescent females with overweight or obesity, compared with their normal-weight counterparts. The association of obesity with menstrual disorders, infertility, and recurrent miscarriages was recognized early [144, 145].

Insulin resistance promotes hyperandrogenemia and decreases the level of steroid hormone binding globulin (SHBG) resulting in elevated levels of free testosterone (discussed above). Aromatization of testosterone to estrogens by aromatase in the adipose tissue suppresses the release of gonadotrophin from the pituitary [140]. Elevated levels of leptin impair follicle development, ovulation, and oocyte maturation in women with obesity [146, 147].

5.2.1 Polycystic ovarian syndrome (PCOS)

This hormonal disorder is one of the most common endocrine disorder in premenopausal women, is also associated with obesity, metabolic syndrome, and T2DM. Irregular periods, anovulatory cycles, oligo-amenorrhea, excess androgen, hirsutism, and polycystic ovaries are the main characteristics of PCOS [148, 149]. Most women with PCOS have elevated levels of plasma free fatty acids, are insulin resistant, and have compensatory hyperinsulinemia. High levels of free fatty acids induce mitochondrial dysfunction, inflammation, oxidative stress, and immune disorders [150]. High levels of plasma free fatty acids cause increased synthesis of androgens in the ovary as well as in the zona reticularis of the adrenal gland. Insulin stimulates androgenesis by stimulating P450c17 activity in zona reticularis of the adrenal gland to produce DHEA and androstenedione [151]. Hyperinsulinemia causes decreased expression of SHBG by hepatocytes (see above), thus further increasing free testosterone levels. Aromatase (CYP19A1) in adipocytes as well as in the tissue of endometriosis converts androgens to estradiol, which inhibits the secretion of gonadotropin releasing hormone, resulting in decreased release FSH and LH from the pituitary. This affects maturation of follicles, production of estrogen, ovulation, maintenance of function of corpus luteum.

Women with PCOS may have problems in conceiving and increased risk of gestational diabetes and miscarriage or premature birth. Impairment of the hypothalamus-pituitary-gonadal (HPG) axis and follicular environment caused by obesity results in fertility problems, miscarriages, and complications in pregnancy.

5.2.2 Anovulation and quality of oocyte

Ovulation disorders account for at least 30% cases of infertility. Menstrual cycle without the release of ovum is called anovulatory cycle. Women with obesity have higher rates of anovulatory menstrual cycles [152, 153], the exact mechanism of which is not known. Common causes of anovulation include hyperandrogenism (as in PCOS, congenital adrenal hyperplasia, androgen-producing tumors), hyperprolactinemia, anorexia, excessive strenuous exercise, stress, thyroid dysfunction, primary pituitary dysfunction, premature ovarian failure, and certain medications. Obesity and strenuous exercise are known to alter profiles of insulin and adiponectin, thus impairing fertility in women. Obese women remain sub-fertile even in the absence of ovulatory dysfunction [154, 155].

Obesity affects the quality of sperm, ovum, embryo, placenta, and the uterine environment. The competence of the oocyte is defined in terms of its ability to become fertilized and support embryo development. Oocyte competence may be influenced by obesity. Machtinger et al. [156] have shown that oocytes from women with obesity are smaller in size, have more abnormal spindles and chromosome misalignment than those from women with normal BMI. Negative outcomes for women undergoing in vitro fertilization (IVF) are more common in women with higher BMI, due to the poor oocyte quality, lower preimplantation rate, and uterine receptivity [157]. Decreased rate of conception, infertility, early pregnancy loss, and reduced success of assisted reproductive technology (ART) have been reported in females with obesity [158].

High serum levels of insulin, insulin resistance, high levels of glucose, lactate, triglycerides, and C-reactive protein in the follicular fluid have a negative impact on oocyte maturation.

Mitochondria of the oocyte must be fully functional, as ATP generated by them are required for oocyte maturation and blastocyst formation. High levels of fuel molecules (glucose, free fatty acids, triglycerides, and cholesterol) in environment increase intracellular lipid accumulation and cause damage to the endoplasmic reticulum and mitochondria. Mice fed on high-fat diet have oocytes with accumulated lipid, increased reactive oxygen species (ROS), and have altered structure of mitochondria [159].

5.2.3 Endometrial hyperplasia

Abnormally thickened lining of the uterus due to disordered proliferation of endometrial glands or endometrial hyperplasia is caused by excess androgen with a relative deficiency of progesterone [160]. Untreated endometrial hyperplasia may develop into endometrial cancer [161]. Endogenous estrogen excess may occur in anovulatory cycles (during perimenopause or PCOS), obesity, and estrogen secreting tumors of the ovary. The most common symptom of endometrial hyperplasia is abnormal uterine bleeding.

5.3 Obesity-related complications in pregnancy

Women with obesity have a higher risk of miscarriage, gestational diabetes, preeclampsia, premature delivery, cesarean section, and post-partum hemorrhage. Maternal obesity with poor glycemic control may result in fetal macrosomia and associated complications. Twenty percent less detection of fetal anomalies has been reported in women with obesity [162].

5.3.1 Risk of miscarriage

A Danish cohort study [163] involving more than 5000 women reported a hazard ratio for miscarriage of 1.23 for women with obesity conceiving spontaneously. Risk of miscarriage is higher in women with obesity who conceive with IVF, even when using donor eggs from women with normal BMI.

5.3.2 Gestational diabetes

Schummers et al. [164] studied 226,000 singleton pregnancies in British Columbia. They have reported an incidence of gestational diabetes of 7.9%. The risk of gestational diabetes was doubled with a BMI > 30, and more than tripled at BMI > 40 kg/m².

5.3.3 Risk of preeclampsia

Women with overweight have double the risk of preeclampsia, while women with obesity have triple the risk, compared with women with normal BMI [164, 165]. Increased physical activity during pregnancy may reduce the risk of both gestational diabetes and preeclampsia.

5.3.4 Preterm labor

Obesity has been shown to increase the risk of preterm delivery [165, 166]. This may be due to increased levels of circulating cytokines and inflammatory proteins in women with obesity.

5.3.5 Cesarean section

The rate of Cesarean section increases with increase in maternal BMI [165, 167]. There is also an increased risk of wound infection, dehiscence, post-partum hemorrhage, and deep vein thrombosis. Duration of labor is longer in women with obesity. There is an increased risk of fetal distress, instrumental delivery, and shoulder dystocia in women with obesity.

6. Economic consequences of obesity

Obesity is a risk factor for various diseases (see above). Expenses on medicine, loss of pay due to absence from work caused by illness, reduced job opportunities, etc., lead to constraint on family budget [168].

6.1 Direct expenses

These include the medical expenses on obesity-related diseases. Expense on medicines for hypertension, type 2 diabetes, dyslipidemia, kidney diseases, stroke; and medical expenses incurred on hospitalization for various conditions affect the family budget as well as the budget of the country [169].

6.2 Indirect expenses

Absence from work due to disease results in decreased pay and early mortality affects the family income. Kjellberg et al. [170] report a 2% decrease in income, 3% increase in social transfer payments, and a 4% increase in healthcare costs per BMI point above 30. Thus, the indirect costs constitute the greatest proportion of total costs associated with obesity. Lee et al. [171] have reported that women with higher BMI are 0.33 times less likely to have service jobs, earn 9% lower monthly wages, and are half as likely to have jobs with bonuses compared with those with normal BMI.

7. Mental and social issues

Obesity is considered a social stigma in most societies. People with obesity are considered responsible for their condition and are often the victims of teasing and bullying, at all ages, from preschool through adolescence to adulthood [172, 173, 174, 175, 176].

7.1 Bullying

Bullying is intentional unprovoked aggression that may be physical (hitting, shoving), mental (name calling, spreading rumors, social exclusion, fat shaming on social media) or both, which causes harm to the victim. It involves an imbalance of physical or psychological power. Weight-based victimization is more common at younger age, but may be observed in adults also [177]. It has been noted that pre-adolescent or adolescent boys with overweight or obesity who are stronger than their peer may show bullying behavior, victimizing those who are physically weaker than them [178].

7.2 Binge eating

Binge eating disorder (BED) is a type of disordered eating in which the individual consumes a relatively large amount of food in a short span of time, compared with other people of the same age, gender, and weight. BED affects 1–3% of the general population. People with BED are 3–6 times more likely to be overweight or obese than persons without eating disorders [179]. Around 30% persons with BED report a history of childhood obesity [180].

7.3 Depression

Meta-analysis conducted by Luppino et al. [181] shows a reciprocal link between depression and obesity. Obesity increases the risk of depression, and depression is predictive of developing obesity. Both obesity and depression are common and both are risk factors for cardiovascular diseases [182]. Depression is also an important cause of premature mortality, primarily due to suicide.

8. Quality of life and mortality

Obesity and the associated diseases affect the quality of life and influence the length of life span [183].

8.1 Decreased quality of life

Health-related quality of life encompasses physical, mental, and social health and is influenced by factors such as socioeconomic status, culture, and environment of the person concerned. The degree of obesity is inversely proportional with the quality of life, as persons with higher BMI values are more likely to have obesity-associated diseases [184].

8.2 Risk of mortality

At least 2.8 million people die annually as a consequence of being overweight or obese. Many complications of obesity are mentioned above that deteriorate the quality of life and may promote early death. Most of the deaths are a direct consequence of cardiovascular problems or cancer [185].

9. Conclusion

Obesity is a condition that can compromise health and is closely associated with various medical conditions caused by increased body mass, metabolic derangement, psychological effects, or economic or social aspects. Awareness about the causes and consequences of obesity should be created among the general public so that persons with obesity may receive timely care with empathy.

Conflict of interest

None.