Open access peer-reviewed chapter - ONLINE FIRST

The Multiple Consequences of Obesity

Written By

Indu Saxena, Amar Preet Kaur, Suwarna Suman, Abhilasha, Prasenjit Mitra, Praveen Sharma and Manoj Kumar

Submitted: January 1st, 2022 Reviewed: March 31st, 2022 Published: May 5th, 2022

DOI: 10.5772/intechopen.104764

IntechOpen
Weight Management - Challenges and Opportunities Edited by Hassan M. Heshmati

From the Edited Volume

Weight Management - Challenges and Opportunities [Working Title]

Dr. Hassan M. Heshmati

Chapter metrics overview

9 Chapter Downloads

View Full Metrics

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.

Keywords

  • obesity
  • metabolic syndrome
  • insulin resistance
  • type 2 diabetes mellitus
  • obesity-related health

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 problemsExamples of associated conditions
Physical problems1. Musculoskeletal disorders
  1. Decreased mobility

  2. Loss of balance

  3. Osteoarthritis

  4. Gout

2. Respiratory problems
  1. Decreased lung compliance

  2. Increased risk of asthma

  3. Sleep apnea

3. Lower limb venous disease
  1. Thrombosis

  2. Varicose veins

  3. Venous insufficiency

4. Skin-related problems
5. Stress incontinence in females
Metabolic disorders1. 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 diseases1. Cholelithiasis
2. Pancreatitis
3. Fatty liver
4. Gastroesophageal reflux disease
Reproductive Health IssuesA. 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 issues1. Increased expense on obesity-related diseases
2. Decreased pay
3. Decreased job opportunity
Mental and social issues1. Social stigma
2. Bullying
3. Binge eating
4. Depression
Quality of life and mortality1. Increased risk of morbidity, mortality decreased quality of life

Table 1.

Multiple consequences of obesity.

Advertisement

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.

Advertisement

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].

Advertisement

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].

Advertisement

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.

Advertisement

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.

Advertisement

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.

Advertisement

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].

Advertisement

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.

Advertisement

Conflict of interest

None.

References

  1. 1. Wang T, Hung CCY, Randall DJ. The comparative physiology of food deprivation: From feast to famine. Annual Review of Physiology. 2006;68:223-225
  2. 2. Van Ginneken VJT, Antonissen E, Muller UK, Booms R, Eding E, Verreth J, et al. Eel migration to the sargasso: Remarkably high swimming efficiency and low energy costs. The Journal of Experimental Biology. 2005;208:1329-1335
  3. 3. Boetius I, Boetius J. Lipid and protein content in Anguilla anguilla during growth and starvation. Dana. 1985;4:1-17
  4. 4. Oka T, Nishimura Y, Zang L, Hirano M, Shimada Y, Wang Z, et al. Diet-induced obesity in zebrafish shares common pathophysiological pathways with mammalian obesity. BMC Physiology. 2010;10:21. DOI: 10.1186/1472-6793-10-21
  5. 5. Hackbarth R. Reptile Diseases. Neptune City (NJ): TFH Publications; 1990
  6. 6. Warwick C. Reptilian disease in relation to artificial environments, with special reference to ethology. International Colloquium on Pathology and Medicine of Reptiles and Amphibians. 1991;4:107-119
  7. 7. Beaufrère H, Nevarez JG, Holder K, Pariaut R, Tully TN, Wakamatsu N. Characterization and classification of psittacine atherosclerotic lesions by histopathology, digital image analysis, transmission and scanning electron microscopy. Avian Pathology. 2011;40(5):531-544
  8. 8. Forhan M, Gill SV. Obesity, functional mobility and quality of life. Best Practice & Research Clinical Endocrinology & Metabolism. 2013;27:129-137. DOI: 10.1016/j.beem.2013.01.003
  9. 9. Finkelstein EA, Chen H, Prabhu M, Trogdon JG, Corso PS. The relationship between obesity and injuries among U.S. adults. American Journal of Health Promotion. 2007;21:460-468
  10. 10. Capodaglio P, Cimolin V, Tacchini E, et al. Balance control and balance recovery in obesity. Current Obesity Reports. 2012;1:166-173. DOI: 10.1007/s13679-012-0018-7
  11. 11. Abramson SB, Attur M. Developments in the scientific understanding of osteoarthritis. Arthritis Research. 2009;11:227-236
  12. 12. Grotle M, Hagen KB, Natvig B, Dahl FA, Kvien TK. Obesity and osteoarthritis in knee, hip and/or hand: An epidemiological study in the general population with 10 years follow-up. BMC Musculoskeletal Disorders. 2008;9(1):1-5
  13. 13. Widmyer MR, Utturkar GM, Leddy HA, Coleman JL, Spritzer CE, Moorman CT III, et al. High body mass index is associated with increased diurnal strains in the articular cartilage of the knee. Arthritis and Rheumatism. 2013;65(10):2615-2622
  14. 14. Fujisawa T, Hattori T, Takahashi K, Kuboki T, Yamashita A, Takigawa M. Cyclic mechanical stress induces extracellular matrix degradation in cultured chondrocytes via gene expression of matrix metalloproteinases and interleukin-1. The Journal of Biochemistry. 1999;125(5):966-975
  15. 15. Fermor B, Weinberg JB, Pisetsky DS, Misukonis MA, Fink C, Guilak F. Induction of cyclooxygenase-2 by mechanical stress through a nitric oxide-regulated pathway. Osteoarthritis and Cartilage. 2002;10(10):792-798
  16. 16. Collins KH, Herzog W, MacDonald GZ, Reimer RA, Rios JL, Smith IC, et al. Obesity, metabolic syndrome, and musculoskeletal disease: Common inflammatory pathways suggest a central role for loss of muscle integrity. Frontiers in Physiology. 2018;9:112. DOI: 10.3389/fphys.2018.00112
  17. 17. Roddy E, Choi HK. Epidemiology of gout. Rheumatic Diseases Clinics of North America. 2014;40(2):155-175
  18. 18. Ter Maaten JC, Voorburg A, Heine RJ, Ter Wee PM, Donker AJ, Gans RO. Renal handling of urate and sodium during acute physiological hyperinsulinaemia in healthy subjects. Clinical Science (London, England). 1997;92(1):51-58
  19. 19. Karlsson C, Lindell K, Ottosson M, Sjöström L, Carlsson B, Carlsson LM. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. The Journal of Clinical Endocrinology and Metabolism. 1998;83(11):3925-3929. DOI: 10.1210/jcem.83.11.5276
  20. 20. Roddy E, Doherty M. Gout and osteoarthritis: A pathogenetic link? Joint, Bone, Spine. 2012;79(5):425-427
  21. 21. Ma CA, Leung YY. Exploring the link between uric acid and osteoarthritis. Frontiers in Medicine (Lausanne). 2017;4:225. DOI: 10.3389/fmed.2017.00225
  22. 22. Leone N, Courbon D, Thomas F, Bean K, Jégo B, Leynaert B, et al. Lung function impairment and metabolic syndrome: The critical role of abdominal obesity. American Journal of Respiratory and Critical Care Medicine. 2009;179(6):509-516
  23. 23. Ochs-Balcom HM, Grant BJ, Muti P, Sempos CT, Freudenheim JL, Trevisan M, et al. Pulmonary function and abdominal adiposity in the general population. Chest. 2006;129(4):853-862
  24. 24. Jones RL, Nzekwu MM. The effects of body mass index on lung volumes. Chest. 2006;130(3):827-833
  25. 25. Beuther DA, Sutherland ER. Overweight, obesity, and incident asthma: A meta-analysis of prospective epidemiologic studies. American Journal of Respiratory and Critical Care Medicine. 2007;175(7):661-666
  26. 26. Sideleva O, Suratt BT, Black KE, Tharp WG, Pratley RE, Forgione P, et al. Obesity and asthma: An inflammatory disease of adipose tissue not the airway. American Journal of Respiratory and Critical Care Medicine. 2012;186(7):598-605
  27. 27. De Blasio MJ, Boije M, Kempster SL, Smith GC, Charnock-Jones DS, Denyer A, et al. Leptin matures aspects of lung structure and function in the ovine fetus. Endocrinology. 2016;157(1):395-404
  28. 28. Sood A, Ford ES, Camargo CA Jr. Association between leptin and asthma in adults. Thorax. 2006;61(4):300-305
  29. 29. Dixon AE, Peters U. The effect of obesity on lung function. Expert Review of Respiratory Medicine. 2018;12(9):755-767. DOI: 10.1080/17476348.2018.1506331
  30. 30. Fimognari FL, Pasqualetti P, Moro L, Franco A, Piccirillo G, Pastorelli R, et al. The association between metabolic syndrome and restrictive ventilatory dysfunction in older persons. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2007;62(7):760-765
  31. 31. Benotti P, Wood GC, Argyropoulos G, Pack A, Keenan BT, Gao X, et al. The impact of obstructive sleep apnea on nonalcoholic fatty liver disease in patients with severe obesity. Obesity (Silver Spring). 2016;24(4):871-877. DOI: 10.1002/oby.21409
  32. 32. Romero-Corral A, Caples SM, Lopez-Jimenez F, Somers VK. Interactions between obesity and obstructive sleep apnea: Implications for treatment. Chest. 2010;137(3):711-719. DOI: 10.1378/chest.09-0360
  33. 33. Willenberg T, Schumacher A, Amann-Vesti B, Jacomella V, Thalhammer C, Diehm N, et al. Impact of obesity on venous hemodynamics of the lower limbs. Journal of Vascular Surgery. 2010;52(3):664-668. DOI: 10.1016/j.jvs.2010.04.023
  34. 34. Danielsson G, Eklof B, Grandinetti A. L. Kistner R. The influence of obesity on chronic venous disease. Vascular and Endovascular Surgery. 2002;36(4):271-276
  35. 35. Davies HO, Popplewell M, Singhal R, Smith N, Bradbury AW. Obesity and lower limb venous disease - The epidemic of phlebesity. Phlebology. 2017;32(4):227-233. DOI: 10.1177/0268355516649333
  36. 36. Ageno W, Piantanida E, Dentali F, Steidl L, Mera V, Squizzato A, et al. Body mass index is associated with the development of the post-thrombotic syndrome. Thrombosis and Haemostasis. 2003;89:305-309
  37. 37. Hansson PO, Eriksson H, Welin L, Svärdsudd K, Wilhelmsen L. Smoking and abdominal obesity: Risk factors for venous thromboembolism among middle-aged men: The study of men born in 1913. Archives of Internal Medicine. 1999;159(16):1886-1890
  38. 38. Kasielska-Trojan A, Sobczak M, Antoszewski B. Risk factors of striae gravidarum. International Journal of Cosmetic Science. 2015;37(2):236-240
  39. 39. Oakley AM, Patel BC. Stretch Marks. Treasure Island (FL): StatPearls Publishing; 2021. p. 2021 Available from:https://www.ncbi.nlm.nih.gov/books/NBK436005/
  40. 40. Waldman RA, Kettler AH. Dermatologic manifestations of obesity: Part I mechanical causes. Journal of Obesity and Weight-loss Medication. 2016;1:010
  41. 41. Kalra MG, Higgins KE, Kinney BS. Intertrigo and secondary skin infections. American Family Physician. 2014;89(7):569-573
  42. 42. Scheinfeld NS. Obesity and dermatology. Clinics in Dermatology. 2004;22(4):303-309. DOI: 10.1016/j.clindermatol.2004.01.001
  43. 43. El Safoury OS, Ibrahim M. A clinical evaluation of skin tags in relation to obesity, type 2 diabetes mellitus, age, and sex. Indian Journal of Dermatology. 2011;56(4):393-397. DOI: 10.4103/0019-5154.84765
  44. 44. Pandey A, Sonthalia S. Skin Tags. Treasure Island (FL): StatPearls Publishing; 2021. p. 2021
  45. 45. Zabawski E, Styles A, Goetz D, Cockerell C. Asymptomatic facial papules and acrochordons of the thighs Birt-Hogg-Dube syndrome. Dermatology Online Journal. 1997;3(2):6
  46. 46. Sachs C, Lipsker D. The molluscum pendulum necklace sign in tuberous sclerosis complex: A case series a pathognomonic finding? Journal of the European Academy of Dermatology and Venereology. 2017;31(11):e507-e508
  47. 47. Pollitzer S. Acanthosis nigricans: A symptom of a disorder of the abdominal sympathetic. Journal of the American Medical Association. 1909;53(17):1369-1373
  48. 48. Robinson SS, Tasker S. Acanthosis nigricans juvenilis associated with obesity; report of a case, with observations on endocrine dysfunction in benign acanthosis nigricans. Archives of Dermatology and Syphilology. 1947;55(6):749-760
  49. 49. Kutlubay Z, Engin B, Bairamov O, Tüzün Y. Acanthosis nigricans: A fold (intertriginous) dermatosis. Clinics in Dermatology. 2015;33(4):466-470
  50. 50. Schilling WH, Crook MA. Cutaneous stigmata associated with insulin resistance and increased cardiovascular risk. International Journal of Dermatology. 2014;53(9):1062-1069
  51. 51. Waldman RA, Kettler AH. Dermatologic manifestations of obesity: Part 2 endocrine abnormalities. Australian Journal of Dermatology. 2016;3(3):1053-1059
  52. 52. Sayed CJ, Hsiao JL, Okun MM. Hidradenitis suppurativa foundation Women's health subcommittee. Clinical epidemiology and Management of Hidradenitis Suppurativa. Obstetrics and Gynecology. 2021;137(4):731-746. DOI: 10.1097/AOG.0000000000004321
  53. 53. Burt Solorzano CM, Knudsen KL, Anderson AD, Hutchens EG, Collins JS, Patrie JT, et al. Insulin resistance, hyperinsulinemia, and LH: Relative roles in peripubertal obesity-associated hyperandrogenemia. The Journal of Clinical Endocrinology and Metabolism. 2018;103(7):2571-2582. DOI: 10.1210/jc.2018-00131
  54. 54. McCartney CR, Prendergast KA, Chhabra S, Eagleson CA, Yoo R, Chang RJ, et al. The association of obesity and hyperandrogenemia during the pubertal transition in girls: Obesity as a potential factor in the genesis of postpubertal hyperandrogenism. The Journal of Clinical Endocrinology and Metabolism. 2006;91(5):1714-1722. DOI: 10.1210/jc.2005-1852
  55. 55. Napolitano M, Megna M, Monfrecola G. Insulin resistance and skin diseases. The Scientific World Journal. 2015;1:247-250. DOI: 10.1155/2015/479354
  56. 56. Poretsky L, Cataldo NA, Rosenwaks Z, Giudice LC. The insulin-related ovarian regulatory system in health and disease. Endocrine Reviews. 1999;20:535-582
  57. 57. Kaspersen KA, Pedersen OB, Petersen MS, Hjalgrim H, Rostgaard K, Møller BK, et al. Obesity and risk of infection: Results from the Danish blood donor study. Epidemiology. 2015;26(4):580-589. DOI: 10.1097/EDE.0000000000000301
  58. 58. Harpsøe MC, Nielsen NM, Friis-Møller N, Andersson M, Wohlfahrt J, Linneberg A, et al. Body mass index and risk of infections among women in the Danish National Birth Cohort. American Journal of Epidemiology. 2016;183(11):1008-1017. DOI: 10.1093/aje/kwv300
  59. 59. Kane H, Lynch L. Innate immune control of adipose tissue homeostasis. Trends in Immunology. 2019;40:857-872. DOI: 10.1016/j.it.2019.07.006
  60. 60. Nakamizo S, Honda T, Kabashima K. Obesity and inflammatory skin diseases. Trends in Immunotherapy. 2017;3(1):98. DOI: 10.24294/ti.v3.i1.98
  61. 61. Hashba H, Bifi J, Thyvalappil A, Sridharan R, Sreenivasan A, Mathew P. Prevalence of metabolic syndrome in patients with lichen planus: A cross-sectional study from a tertiary care center. Indian Dermatology Online Journal. 2018;9(5):304-308. DOI: 10.4103/idoj.IDOJ_27_18
  62. 62. Subak LL, Richter HE, Hunskaar S. Obesity and urinary incontinence: Epidemiology and clinical research update. The Journal of Urology. 2009;182( Suppl. 6):S2-S7. DOI: 10.1016/j.juro.2009.08.071
  63. 63. Bays HE, Gonzalez-Campoy JM, Bray GA, Kitabchi AE, Bergman DA, Schorr AB, et al. Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity. Expert Review of Cardiovascular Therapy. 2008;6(3):343-368
  64. 64. Cinti S. The adipose organ at a glance. Disease Models & Mechanisms. 2012;5(5):588-594. DOI: 10.1242/dmm.009662
  65. 65. Ishibashi J, Seale P. Medicine Beige can be slimming. Science. 2010;328:1113-1114
  66. 66. Petrovic N, Walden TB, Shabalina IG, Timmons JA, Cannon B, Nedergaard J. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes. Journal of Biological Chemistry. 2015;285(10):7153-7164. DOI: 10.1074/jbc.M109.053942
  67. 67. Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-468
  68. 68. Shan T, Liang X, Bi P, Zhang P, Liu W, Kuang S. Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues. Journal of Lipid Research. 2013;54(8):2214-2224. DOI: 10.1194/jlr.M038711
  69. 69. Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metabolism. 2018;27(1):68-83. DOI: 10.1016/j.cmet.2017.12.002
  70. 70. Monzon JR, Basile R, Heneghan S, Udupi V, Green A. Lipolysis in adipocytes isolated from deep and superficial subcutaneous adipose tissue. Obesity Research. 2002;10(4):266-269
  71. 71. Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: Peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. The Journal of Clinical Endocrinology and Metabolism. 2004;89(2):463-478. DOI: 10.1210/jc.2003-030723
  72. 72. Available from:https://analyzedirect.com/documents/guides/adipose_tissue_classification_and_quantification.pdf
  73. 73. Shen W, Wang Z, Punyanita M, Lei J, Sinav A, Kral JG, et al. Adipose tissue quantification by imaging methods: A proposed classification. Obesity Research. 2003;11(1):5-16. DOI: 10.1038/oby.2003.3
  74. 74. Hausman DB, DiGirolamo M, Bartness TJ, Hausman GJ, Martin RJ. The biology of white adipocyte proliferation. Obesity Reviews. 2001;2:239-254
  75. 75. Wang Q , Imam MU, Yida Z, Wang F. Peroxisome proliferator-activated receptor gamma (PPARγ) as a target for concurrent management of diabetes and obesity-related cancer. Current Pharmaceutical Design. 2017;23:3677-3688. DOI: 10.2174/138161282366617070412510
  76. 76. Rey-López JP, de Rezende LF, Pastor-Valero M, Tess BH. The prevalence of metabolically healthy obesity: A systematic review and critical evaluation of the definitions used. Obesity Reviews. 2014;15:781-790. DOI: 10.1111/obr.12198
  77. 77. Stenkula KG, Erlanson-Albertsson C. Adipose cell size: Importance in health and disease. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology. 2018;315:R284-R295
  78. 78. Misra A, Vikram NK. Clinical and pathophysiological consequences of abdominal adiposity and abdominal adipose tissue depots. Nutrition. 2003;19:457-466
  79. 79. Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nature Reviews. Immunology. 2011;11(2):85-97
  80. 80. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation. 2003;112:1796-1808. DOI: 10.1172/JCI200319246
  81. 81. Blouin K, Nadeau M, Perreault M, Veilleux A, Drolet R, Marceau P, et al. Effects of androgens on adipocyte differentiation and adipose tissue explant metabolism in men and women. Clinical Endocrinology. 2010;72(2):176-188
  82. 82. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55(Supplement 2):S9-S15
  83. 83. Snel M, Jonker JT, Schoones J, Lamb H, de Roos A, Pijl H, et al. Ectopic fat and insulin resistance: Pathophysiology and effect of diet and lifestyle interventions. International Journal of Endocrinology. 2012;2012(7):983814. DOI: 10.1155/2012/983814
  84. 84. Morawietz H, Bornstein SR. Leptin, endothelin, NADPH oxidase, and heart failure. Hypertension. 2006;47(5):e20-e21
  85. 85. Barone I, Giordano C, Bonofiglio D, Andò S, Catalano S. Leptin, obesity and breast cancer: Progress to understanding the molecular connections. Current Opinion in Pharmacology. 2016;31:83-89. DOI: 10.1016/j.coph.2016.10.003
  86. 86. Saxena NK, Taliaferro-Smith L, Knight BB, et al. Bidirectional crosstalk between leptin and insulin-like growth factor-I signaling promotes invasion and migration of breast cancer cells via transactivation of epidermal growth factor receptor. Cancer Research. 2008;68:9712-9722. DOI: 10.1158/0008-5472.CAN-08-1952
  87. 87. Mori H, Hanada R, Hanada T, Aki D, Mashima R, Nishinakamura H, et al. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nature Medicine. Jul 2004;10(7):739-743
  88. 88. Noel P, Patel K, Durgampudi C, Trivedi RN, de Oliveira C, Crowell MD, et al. Peripancreatic fat necrosis worsens acute pancreatitis independent of pancreatic necrosis via unsaturated fatty acids increased in human pancreatic necrosis collections. Gut. 2016;65:100-111
  89. 89. Sarwar R, Pierce N, Koppe S. Obesity and nonalcoholic fatty liver disease: Current perspectives. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 2018;11:533-542. DOI: 10.2147/DMSO.S146339
  90. 90. Chait A, den Hartigh LJ. Adipose tissue distribution, inflammation and its metabolic consequences, including diabetes and cardiovascular disease. Frontiers in Cardiovascular Medicine. 2020;7:22. DOI: 10.3389/fcvm.2020.00022
  91. 91. Qi XY, Qu SL, Xiong WH, Rom O, Chang L, Jiang Z-S. Perivascular adipose tissue (PVAT) in atherosclerosis: A double-edged sword. Cardiovascular Diabetology. 2018;17(134):1-20. DOI: 10.1186/s12933-018-0777-x
  92. 92. Hursting SD, Digiovanni J, Dannenberg AJ, et al. Obesity, energy balance, and cancer: New opportunities for prevention. Cancer Prevention Research (Philadelphia, Pa.). 2012;5:1260-1272
  93. 93. Bhaskaran K, Douglas I, Forbes H, et al. Body- mass index and risk of 22 specific cancers: A population-based cohort study of 5.24 million UK adults. Lancet. 2014;384:755-765
  94. 94. Niedermaier T, Behrens G, Schmid D, Schlecht I, Fischer B, Leitzmann MF. Body mass index, physical activity, and risk of adult meningioma and glioma: A meta-analysis. Neurology. 2015;85(15):1342-1350. DOI: 10.1212/WNL.0000000000002020
  95. 95. Solinas G, Karin M. JNK1 and IKKbeta: Molecular links between obesity and metabolic dysfunction. The FASEB Journal. 2010;24:2596-2611
  96. 96. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, et al. Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell. 2010;140:338-348
  97. 97. Iyengar NM, Hudis CA, Dannenberg AJ. Obesity and cancer: Local and systemic mechanisms. Annual Review of Medicine. 2015;66:297-309
  98. 98. Lonergan PE, Tindall DJ. Androgen receptor signaling in prostate cancer development and progression. Journal of Carcinogenesis. 2011;10:20
  99. 99. Subbaramaiah K, Morris PG, Zhou XK, et al. Increased levels of COX-2 and prostaglandin E2 contribute to elevated aromatase expression in inflamed breast tissue of obese women. Cancer Discovery. 2012;2:356-365
  100. 100. Irahara N, Miyoshi Y, Taguchi T, et al. Quantitative analysis of aromatase mRNA expression derived from various promoters (I.4, I.3, PII and I.7) and its association with expression of TNF-alpha, IL-6 and COX-2 mRNAs in human breast cancer. International Journal of Cancer. 2006;118:1915-1921
  101. 101. Brown KA, McInnes KJ, Hunger NI, et al. Subcellular localization of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 provides a link between obesity and breast cancer in postmenopausal women. Cancer Research. 2009;69:5392-5399
  102. 102. Randi G, Franceschi S, La Vecchia C. Gallbladder cancer worldwide: Geographical distribution and riskfactors. International Journal of Cancer. 2006;118(7):1591-1602
  103. 103. Bishayee A. The role of inflammation and liver cancer. Advances in Experimental Medicine and Biology. 2014;816:401-435
  104. 104. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer ina prospectively studied cohort of U.S. adults. New England Journal of Medicine. 2003;348(17):1625-1638
  105. 105. Schmitz KH, Neuhouser ML, Agurs-Collins T, Zanetti KA, Cadmus-Bertram L, Dean LT, et al. Impact of obesity on cancer survivorship and the potential relevance of race and ethnicity. Journal of the National Cancer Institute. 2013;105(18):1344-1354. DOI: 10.1093/jnci/djt223
  106. 106. Paskett ED, Dean JA, Oliveri JM, Harrop JP. Cancer-related lymphedema risk factors, diagnosis, treatment, and impact: A review. Journal of Clinical Oncology. 2012;30(30):3726-3733
  107. 107. Gacci M, Sebastianelli A, Salvi M, et al. Role of abdominal obesity for functional outcomes andcomplications in men treated with radical prostatectomy for prostate cancer: Results of the MulticenterItalian report on radical prostatectomy (MIRROR) study. Scandinavian Journal of Urology. 2014;48(2):138-145
  108. 108. Meyerhardt JA, Tepper JE, Niedzwiecki D, et al. Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: Findings from intergroup trial 0114. Journal of Clinical Oncology. 2004;22(4):648-657
  109. 109. Teras LR, Kitahara CM, Birmann BM, et al. Body size and multiple myeloma mortality: A pooled analysisof 20 prospective studies. British Journal of Haematology. 2014;166(5):667-676
  110. 110. Zang EA, Wynder EL. The association between body mass index and the relative frequencies of diseases in a sample of hospitalized patients. Nutrition and Cancer. 1994;21:247-261
  111. 111. Cheung N, Wong TY. Obesity and eye diseases. Survey of Ophthalmology. 2007;52(2):180-195
  112. 112. Klein BE, Klein R, Linton KL. Intraocular pressure in an American community. The beaver dam eye study. Investigative Ophthalmology & Visual Science. 1992;33:2224-2228
  113. 113. Mori K, Ando F, Nomura H, et al. Relationship between intraocular pressure and obesity in Japan. International Journal of Epidemiology. 2000;29:661-666
  114. 114. Age-Related Eye Disease Study Research Group. Risk factors associated with age-related macular degeneration. A case-control study in the age-related eye disease study: Age-related eye disease study report number 3. Ophthalmology. 2000;107:2224-2232
  115. 115. Spaide RF, Armstrong D, Browne R. Continuing medical education review: Choroidal neovascularization in age-related macular degeneration--what is the cause? Retina. 2003;23:595-614
  116. 116. van Leiden HA, Dekker JM, Moll AC, et al. Blood pressure, lipids, and obesity are associated with retinopathy: The Hoorn study. Diabetes Care. 2002;25:1320-1325
  117. 117. Wong TY, Larsen EK, Klein R, et al. Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: The atherosclerosis risk in Communities & Cardiovascular Health studies. Ophthalmology. 2005;112:540-547
  118. 118. Teuscher AU, Meienberg O. Ischaemic oculomotor nerve palsy. Clinical features and vascular risk factors in 23 patients. Journal of Neurology. 1985;232:144-149
  119. 119. Raina J, Foster JA. Obesity as a cause of mechanical entropion. American Journal of Ophthalmology. 1996;122:123-125
  120. 120. Krispel CM, Keltner JL, Smith W, Chu DG, Ali MR. Undiagnosed papilledema in a morbidly obese patient population: A prospective study. Journal of Neuro-Ophthalmology. 2011;31:310-315
  121. 121. Kristinsson JK, Carlson AN, Kim T. Keratoconus and obesity-a connection? Investigative Ophthalmology & Visual Science. 2003;44:812
  122. 122. Venneman NG, van Erpecum KJ. Pathogenesis of gallstones. Gastroenterology Clinics of North America. 2010;39:171-183
  123. 123. Py S, Hsu YC, Cheng YF, Kor CT, Su WW. Strong association between metabolically-abnormal obesity and gallstone disease in adults under 50 years. BMC Gastroenterol. 2019;19:117. DOI: 10.1186/s12876-019-1032-y
  124. 124. Lammert F, Gurusamy K, Ko CW, Miquel JF, Mendez-Sanchez N, Portincasa P, et al. Gallstones. Nature Reviews Disease Primers. 2016;2:16024. DOI: 10.1038/nrdp.2016.24
  125. 125. Pariente A, Erlinger S. Cholelithiasis and obesity: Epidemiology, pathophysiology, clinical manifestations and prevention. Hepato-Gastro Oncologie Digestive. 2017;24(1):18-25. DOI: 10.1684/hpg.2016.1395
  126. 126. El-Serag HB, Hashmi A, Garcia J, Richardson P, Alsarraj A, Fitzgerald S, et al. Visceral abdominal obesity measured by CT scan is associated with an increased risk of Barrett's oesophagus: A case-control study. Gut. 2014;63(2):220-229
  127. 127. Emerenziani S, Rescio MP, Guarino MP, Cicala M. Gastro-esophageal reflux disease and obesity, where is the link? World Journal of Gastroenterology. 2013;19(39):6536-6539. DOI: 10.3748/wjg.v19.i39.6536
  128. 128. Eisenberg ML, Kim S, Chen Z, Sundaram R, Schisterman EF, Buck Louis GM. The relationship between male BMI and waist circumference on semen quality: Data from the LIFE study. Human Reproduction. 2014;29(2):193-200. DOI: 10.1093/humrep/det428
  129. 129. Amiri M, Ramezani TF. Potential adverse effects of female and male obesity on fertility: A narrative review. International Journal of Endocrinology and Metabolism. 2020;18(3):e101776. DOI: 10.5812/ijem.101776
  130. 130. Glenn T, Harris AL, Lindheim SR. Impact of obesity on male and female reproductive outcomes. Current Opinion in Obstetrics and Gynecology. 2019;31(4):201-206. DOI: 10.1097/GCO.0000000000000549
  131. 131. De Lorenzo A, Noce A, Moriconi E, Rampello T, Marrone G, Di Daniele N, et al. MOSH syndrome (male obesity secondary hypogonadism): Clinical assessment and possible therapeutic approaches. Nutrients. 12 Apr 2018;10(4):474. DOI: 10.3390/nu10040474
  132. 132. Tremellen K. Gut endotoxin leading to a decline IN Gonadal function (GELDING) - a novel theory for the development of late onset hypogonadism in obese men. Basic and Clinical Andrology. 2016;26(1):1-13
  133. 133. Dohle GR, Arver S, Bettocchi C, Jones TH, Kliesch S. EAU guidelines in male hypogonadism. European Association of Urology. 2015;3:242-252
  134. 134. Costanzo PR, Pacenza NA, Aszpis SM, Suárez SM, Pragier UM, Usher JGS, et al. Clinical and etiological aspects of gynecomastia in adult males: A multicenter study. BioMed Research International. 2018;1:1-7. DOI: 10.1155/2018/8364824
  135. 135. Isidori AM, Caprio M, Strollo F, et al. Leptin and androgens in male obesity: Evidence for leptin contribution to reduced androgen levels. The Journal of Clinical Endocrinology and Metabolism. 1999;84:3673-3680
  136. 136. Hrabovszky E, Ciofi P, Vida B, et al. The kisspeptin system of the human hypothalamus: Sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. European Journal of Neuroscience. 2010;31:1984-1998
  137. 137. Ohtaki T, Shintani Y, Honda S, et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411:613-724
  138. 138. Dhillo WS, Chaudhri OB, Patterson M, et al. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. The Journal of Clinical Endocrinology and Metabolism. 2005;90:6609-6615
  139. 139. George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: Kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clinical Endocrinology. 2013;79:100-104
  140. 140. Cohen PG. The hypogonadal-obesity cycle: Role of aromatase in modulating the testosterone-estradiol shunt—A major factor in the genesis of morbid obesity. Medical Hypotheses. 1999;52:49-51
  141. 141. Janiszewski PM, Janssen I, Ross R. Abdominal obesity and physical inactivity are associated with erectile dysfunction independent of body mass index. The Journal of Sexual Medicine. 2009;6:1990-1998
  142. 142. Sermondade N, Faure C, Fezeu L, Shayeb AG, Bonde JP, Jensen TK, et al. BMI in relation to sperm count: An updated systematic review and collaborative meta-analysis. Human Reproduction Update. 2013;19(3):221-231
  143. 143. Tunc O, Bakos HW, Tremellen K. Impact of body mass index on seminal oxidative stress. Andrologia. 2011;43:121-128
  144. 144. Silvestris E, de Pergola G, Rosania R, Loverro G. Obesity as disruptor of the female fertility. Reproductive Biology and Endocrinology. 2018;16(1):22. DOI: 10.1186/s12958-018-0336-z
  145. 145. Broughton DE, Moley KH. Obesity and female infertility: Potential mediators of obesity's impact. Fertility and Sterility. 2017;107(4):840-847. DOI: 10.1016/j.fertnstert.2017.01.017
  146. 146. Practice Committee of the American Society for Reproductive Medicine. Obesity and reproduction: A committee opinion. Fertility and Sterility. 2015;104(5):1116-1126
  147. 147. Duggal PS, Van Der Hoek KH, Milner CR, Ryan NK, Armstrong DT, Magoffin DA, et al. The in vivo and in vitro effects of exogenous leptin on ovulation in the rat. Endocrinology. 2000;141(6):1971-1976. DOI: 10.1210/endo.141.6.7509
  148. 148. Dunaif A. Insulin resistance and the polycystic ovary syndrome: Mechanism and implications for pathogenesis. Endocrine Reviews. 1997;18(6):774-800. DOI: 10.1210/edrv.18.6.0318
  149. 149. Cano F, Garcia-Velasco JA, Millet A, Remohi J, Simon C, Pellicer A. Oocyte quality in polycystic ovaries revisited: Identification of a particular subgroup of women. Journal of Assisted Reproduction and Genetics. 1997;14(5):254-261. DOI: 10.1007/BF02765826
  150. 150. Carpentier AC. Postprandial fatty acid metabolism in the development of lipotoxicity and type 2 diabetes. Diabetes & Metabolism. 2008;34(2):97-107
  151. 151. Tee MK, Dong Q , Miller WL. Pathways leading to phosphorylation of p450c17 and to the posttranslational regulation of androgen biosynthesis. Endocrinology. 2008;149(5):2667-2677
  152. 152. Parihar M. Obesity and infertility. Reviews in Gynaecological Practice. 2003;3:120-126
  153. 153. Giviziez CR, Sanchez EG, Approbato MS, Maia MC, Fleury EA, Sasaki RS. Obesity and anovulatory infertility: A review. JBRA Assisted Reproduction. 2016;20(4):240-245. DOI: 10.5935/1518-0557.20160046
  154. 154. Wise LA, Rothman KJ, Mikkelsen EM, Sorensen HT, Riis A, Hatch EE. An internet-based prospective study of body size and time-to-pregnancy. Human Reproduction. 2010;25:253-264
  155. 155. Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to pregnancy. Human Reproduction. 2007;22:414-420
  156. 156. Machtinger R, Combelles CM, Missmer SA, Correia KF, Fox JH, Racowsky C. The association between severe obesity and characteristics of failed fertilized oocytes. Human Reproduction. 2012;27(11):3198-3207
  157. 157. Bellver J, Ayllon Y, Ferrando M, Melo M, Goyri E, Pellicer A, et al. Female obesity impairs in vitro fertilization outcome without affecting embryo quality. Fertility and Sterility. 2010;93:447-454
  158. 158. Luke B, Brown MB, Stern JE, Missmer SA, Fujimoto VY, Leach R. SART writing group. Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates. Human Reproduction. 2011;26(1):245-252
  159. 159. Igosheva N, Abramov AY, Poston L, Eckert JJ, Fleming TP, Duchen MR, et al. Maternal diet-induced obesity alters mitochondrial activity and redox status in mouse oocytes and zygotes. PLoS One. 2010;5(4):e10074
  160. 160. Parkash V, Fadare O, Tornos C, WG MC. Committee Opinion No. 631: Endometrial Intraepithelial Neoplasia. Obstetrics & Gynecology. 2015;126(4):897. DOI: 10.1097/AOG.0000000000001071
  161. 161. Siegel RL, Miller KD, Jemal A. Cancer statistics. A Cancer Journal for Clinicians. 2018;68(1):7-30. DOI: 10.3322/caac.21442
  162. 162. American College of Obstetricians and Gynecologists. ACOG practice bulletin no 156: Obesity in pregnancy. Obstetrics & Gynecology. 2015;126:e112-e126
  163. 163. Hahn KA, Hatch EE, Rothman KJ, Mikkelsen EM, Brogly SB, Sørensen HT, et al. Body size and risk of spontaneous abortion among Danish pregnancy planners. Paediatric and Perinatal Epidemiology. 2014;28(5):412-423
  164. 164. Schummers L, Hutcheon JA, Bodnar LM, Lieberman E, Himes KP. Risk of adverse pregnancy outcomes by prepregnancy body mass index: A population-based study to inform prepregnancy weight loss counseling. Obstetrics and Gynecology. 2015;125(1):133
  165. 165. Marchi J, Berg M, Dencker A, Olander EK, Begley C. Risks associated with obesity in pregnancy, for the mother and baby: A systematic review of reviews. Obesity Reviews. 2015;16(8):621-638
  166. 166. Lutsiv O, Mah J, Beyene J, McDonald SD. The effects of morbid obesity on maternal and neonatal health outcomes: A systematic review and meta-analyses. Obesity Reviews. 2015;16(7):531-546
  167. 167. Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH, et al. Obesity, obstetric complications and cesarean delivery rate–a population-based screening study. American Journal of Obstetrics and Gynecology. 2004;190(4):1091-1097
  168. 168. Spieker EA, Pyzocha N. Economic impact of obesity. Primary Care. 2016;43(1):83-95. DOI: 10.1016/j.pop.2015.08.013
  169. 169. Thompson D, Edelsberg J, Colditz GA, Bird AP, Oster G. Lifetime health and economic consequences of obesity. Archives of Internal Medicine. 1999;159(18):2177-2183. DOI: 10.1001/archinte.159.18.2177
  170. 170. Kjellberg J, Tange LA, Ibsen R, Højgaard B. The socioeconomic burden of obesity. Obesity Facts. 2017;10:493-502. DOI: 10.1159/000480404
  171. 171. Lee H, Ahn R, Kim TH, Han E. Impact of obesity on employment and wages among young adults: Observational study with panel data. International Journal of Environmental Research and Public Health. 2019;16(1):139. DOI: 10.3390/ijerph16010139
  172. 172. Leeper L. Body size stigmatization in preschool children: The role of control attributions. Journal of Pediatric Psychology. 2004;29:613-620
  173. 173. Klesges RC, Haddock CK, Stein RJ, Klesges LM, Eck LH, et al. Relationship between psychosocial functioning and body fat in preschool children: A longitudinal investigation. Journal of Consulting and Clinical Psychology. 1992;60:793-796
  174. 174. Pierce JW, Wardle J. Cause and effect beliefs and self-esteem of overweight children. Journal of Child Psychology and Psychiatry. 1997;38:645-650
  175. 175. Van Geel M, Vedder P, Tanilon J. Are overweight and obese youths more often bullied by their peers? A meta-analysis on the relation between weight status and bullying. International Journal of Obesity. 2014;38:1263-1267
  176. 176. Puhl RM, Brownell KD. Bias, discrimination, and obesity. Obesity Research. 2001;9:788-805
  177. 177. Bacchini D, Licenziati MR, Garrasi A, Corciulo N, Driul D, Tanas R, et al. Bullying and victimization in overweight and obese outpatient children and adolescents: An Italian multicentric study. PLoS One. 2015;10(11):e0142715. DOI: 10.1371/journal.pone.0142715
  178. 178. Griffiths LJ, Wolke D, Page AS, Horwood P. Obesity and bullying: Different effects for boys and girls. Archives of Disease in Childhood. 2006;91:121-125
  179. 179. Kessler RC, Berglund PA, Chiu WT, Deitz AC, Hudson JI, Shahly V, et al. The prevalence and correlates of binge eating disorder in the World Health Organization world mental health surveys. Biological Psychiatry. 2013;73(9):904-914
  180. 180. Jacobi C, Hayward C, de Zwaan M, Kraemer HC, Agras WS. Coming to terms with risk factors for eating disorders: Application of risk terminology and suggestions for a general taxonomy. Psychological Bulletin. 2004;130(1):19-65
  181. 181. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, obesity, and depression: A systematic review and meta-analysis of longitudinal studies. Archives of General Psychiatry. 2010;67(3):220-229. DOI: 10.1001/archgenpsychiatry.2010.2
  182. 182. Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, et al. Depression and cardiac mortality: Results from a community-based longitudinal study. Archives of General Psychiatry. 2001;58(3):221-227
  183. 183. Taylor VH, Forhan M, Vigod SN, McIntyre RS, Morrison KM. The impact of obesity on quality of life. Best Practice & Research. Clinical Endocrinology & Metabolism. 2013;27(2):139-146
  184. 184. Stephenson J, Smith CM, Kearns B, et al. The association between obesity and quality of life: A retrospective analysis of a large-scale population-based cohort study. BMC Public Health. 2021;21(1):1-9. DOI: 10.1186/s12889-021-12009-8
  185. 185. De Gonzalez AB, Hartge P, Cerhan JR, Flint AJ, Hannan L, MacInnis RJ, et al. Body-mass index and mortality among 1.46 million white adults. NEJM. 2010;363(23):2211-2219

Written By

Indu Saxena, Amar Preet Kaur, Suwarna Suman, Abhilasha, Prasenjit Mitra, Praveen Sharma and Manoj Kumar

Submitted: January 1st, 2022 Reviewed: March 31st, 2022 Published: May 5th, 2022