Introduction

The adipose tissue is the largest endocrine organ in humans. It is mainly located beneath the skin (subcutaneous adipose tissue) but also in other areas (e.g., visceral adipose tissue and ectopic adipose tissue) [1-5]. It plays a vital role in the survival of humans. In addition to its mechanical and storage properties, adipose tissue has important metabolic and endocrine functions.

Excess adiposity is defined as the expansion of adipose tissue (e.g., hypertrophy and hyperplasia) leading to overweight/obesity and subsequent morbidity and mortality [6-8]. Obesity is a major health problem worldwide inflicting high cost to the society [9,10].

Management of excess adiposity requires multidisciplinary approaches including lifestyle (e.g., diet, exercise, and behavioral change), food supplements, drugs, medical devices, gut microbiome modulation, body contouring, and bariatric surgery [6,11-24].

Normal Adipose Tissue

The adipose tissue is the largest endocrine organ in humans (Figure 1). In normal young adults, the adipose tissue represents 8 to 19% of total body mass in men and 21 to 32% in women. It contains adipocytes, connective tissue, nerve tissue, vascular cells, and immune cells [2,5]. There are three types of adipose tissue, white adipose tissue (the predominant type), brown adipose tissue, and beige adipose tissue (new classification) [1-5].

Figure 1: The adipose tissue is the largest endocrine organ in humans. Copyright katerynakon (Kateryna Kon)/Depositphotos Inc.

Distribution

White Adipose Tissue

The white adipose tissue is located beneath the skin (subcutaneous adipose tissue) and other areas (e.g., visceral adipose tissue and ectopic adipose tissue) [1-5,25]. The subcutaneous white adipose tissue is the most abundant component of adipose tissue in lean subjects, representing approximately 80% of total adipose tissue (Figure 2). The visceral white adipose tissue is localized around several internal organs (e.g., epicardial adipose tissue). The ectopic white adipose tissue is localized within internal organs (e.g., liver and pancreas). These adipose tissues represent 6 to 20% of total adipose tissue.

Figure 2: The subcutaneous white adipose tissue represents approximately 80% of total adipose tissue in lean subjects. Copyright tussiksmail.gmail.com (Victor Josan)/Depositphotos Inc.

Brown Adipose Tissue

The brown adipose tissue is located primarily in the cervical, axillary, and paraspinal regions [1,2,5,25]. Brown adipose tissue represents approximately 1-2% of total adipose tissue [5].

Beige Adipose Tissue

The beige adipose tissue represents a new classification. It has been described as the presence of brown adipocytes within white adipose tissue [4,5].

Regulation

The white, brown, and beige adipose tissues are innervated by the sympathetic nervous system whose activation is necessary for the functions of different adipose tissues [4]. The metabolism of adipose tissue is also influenced by several hormones including growth hormone, leptin, insulin, and cortisol (non-exhaustive list).

Role

The white adipose tissue plays a vital role in the survival of humans. It is involved in heat insulation, dermal infection barrier, mechanical protection (cushion), and storage of excess energy as triglycerides. It is a highly active metabolic and endocrine organ involved in the production of adipocytokines (e.g., leptin, adiponectin, resistin, omentin, interleukin 6, and tumor necrosis factor alpha) which act at both local (autocrine, paracrine) and systemic (endocrine) levels, affecting energy homeostasis, insulin sensitivity, and neuroendocrine, cardiovascular, and immune functions (Figure 3) [1,2,4,5,25].

Figure 3. The white adipose tissue produces several factors called adipocytokines with autocrine, paracrine, and endocrine functions. Copyright edesignua (Tetiana Zhabska)/Depositphotos Inc.

The brown adipose tissue is involved in thermoregulation. It transfers energy from food into heat [1,4,5]. Although the mass of the brown adipose is relatively small, its contribution to metabolic health is important. It produces adipocytokines and exclusively secretes molecules called batokines (e.g., fibroblast growth factor). The exact role of the beige adipose tissue has yet to be determined [4,5].

Physiological Variations

Age

With aging, adipose tissue undergoes significant changes in mass, distribution, composition, and secretory profile due to chronic positive calorie balance, reduced physical activity, and lower basal metabolic rate [1,2,4,25,26]. White adipose tissue mass increases, peaks around 65-70 years, but decreases in very old ages. The increase in visceral adipose tissue mass is more pronounced in women [26]. There is an increase in the levels of most adipocytokines (e.g., leptin, adiponectin, resistin, interleukin 6, and tumor necrosis factor alpha) with aging [25]. Elevated levels of pro-inflammatory adipocytokines (e.g., interleukin 6 and tumor necrosis factor alpha) can negatively impact aging and lifespan by promoting chronic diseases (e.g., obesity, type 2 diabetes, and ischemic heart disease). In contrast, elevated levels of adiponectin, an anti-inflammatory adipocytokine, can be beneficial and responsible for the favorable metabolic phenotype of centenarians, explaining their extended longevity. Brown adipose tissue and beige adipose tissue masses also decrease with aging.

Gender

Overall, men have a lower total body adipose tissue percentage than premenopausal women but have more adipose tissue in the abdominal subcutaneous and visceral areas [3,25].

Disorders of Adipose Tissue

Disorders of adipose tissue affect mainly white adipose tissue. They include accumulation of lipophilic endocrinedisrupting chemicals (EDCs) responsible for several medical disorders, excess adiposity (e.g., hypertrophy and hyperplasia) leading to overweight/obesity and related comorbidities, and deficient adiposity (e.g., lipodystrophies).

Accumulation of EDCs

EDCs are a heterogenous group of exogenous chemicals or chemical mixtures that interfere with the action of hormones. EDCs are present in a variety of products [27]. The majority of EDCs are highly lipophilic, stored in adipose tissue, and resistant to degradation. The chronic release of EDCs stored in adipose tissue can promote several medical disorders including diabetes, obesity, nonalcoholic fatty liver disease, infertility, and cancers (non-exhaustive list) [27].

Excess Adiposity

The body mass index (BMI) is used as a surrogate marker for adipose tissue mass and for defining overweight/obesity [6]. Overweight is defined as a BMI ≥ 25 and < 30 kg/m² and obesity as a BMI ≥ 30 kg/m². In some Asian countries (e.g., China and Japan), the thresholds to define overweight and obesity are lower.

The BMI may not be an accurate tool to assess obesity since it does not take body composition into account.

The expansion of the adipose tissue occurs when energy intake exceeds energy expenditure. The adipose tissue can expand by either hypertrophy (increase in the size of adipocytes) or hyperplasia (increase in the number of adipocytes). The excess adiposity leads to overweight/obesity. The subcutaneous white adipose tissue acts as a buffer for excess lipid storage (Figure 4). When this storage capacity is exceeded due to limited hypertrophy or hyperplasia, the excess fat accumulates outside of the subcutaneous area, causing visceral obesity. Obesity is a major health problem worldwide. Its prevalence has doubled in more than 70 countries since 1980 [8]. The number of adult subjects with obesity is around 650 million worldwide.

Figure 4: Excess fat deposits in the subcutaneous areas. Copyright CLIPAREA (Peter Lecko)/Depositphotos Inc.

Causes

The pathogenesis of excess adiposity leading to obesity is complex. Several factors can contribute (e.g., genetic, sociocultural, behavioral, environmental, and medical factors) (non-exhaustive list) [6].

Consequences

Excess adiposity leading to obesity is associated with increased morbidity/mortality and high cost for the society [6-10]. Multiple organs and systems are impacted by obesity (Figure 5) (Table 1). Visceral obesity is strongly associated with cardiometabolic risk factors, especially in women [28]. Nearly 4 million subjects die each year from the consequences of obesity. People with obesity spend approximately 30% more on medical care than people without obesity. The annual worldwide cost of obesity is more than $2 trillion.

Figure 5: Organs impacted by obesity (non-exhaustive list). Copyright Kittichai (Kittichai Songprakob)/Depositphotos Inc.

Table 1: Systems impacted by obesity and the resulting comorbidities (non-exhaustive list).

Management

In addition to preventive measures, management of excess adiposity requires multidisciplinary approaches including lifestyle (e.g., diet, exercise, and behavioral change), food supplements, drugs, medical devices, gut microbiome modulation, body contouring, and bariatric surgery (Table 2) [6,11-24].

Table 2. Anti-obesity tools approved and/or available in the USA (non-exhaustive list).

Any medical condition that can contribute to weight gain should be treated as appropriate. Subjects receiving medications known to induce weight gain should consider alternative treatment when possible.

Even a modest weight loss can decrease the risk of several comorbidities of obesity [6,29]. The ideal is a weight loss of at least 5 to 10% over 6 to 9 months followed by a long-lasting weight maintenance. Unfortunately, many subjects do not achieve longlasting benefits of weight loss due to difficulty with compliance as well as body adaptation in response to weight loss.

Lifestyle

For a clinically meaningful weight loss, an intense lifestyle intervention that includes in-person individual or group sessions is recommended [6]. Diet is an important component in the management of obesity (Figure 6). Several hypocaloric diets have been proposed. They differ in the amount of calorie (e.g., low calorie or very-low calorie) and macronutrient composition (e.g., low or high carbohydrate, low or high fat, and high protein) [11]. Hypocaloric diets result in weight loss regardless of macronutrient composition. The extent of caloric restriction should be adjusted to the baseline caloric intake and the physical activity.

Figure 9: Obesity is associated with important changes in gut microbiome (dysbiosis). Copyright ovocheva (Zhanna Kocherzhuk)/Depositphotos Inc.

Gut microbiome can be modulated to change the host metabolism and manage obesity. The tools include diet, prebiotics, probiotics, synbiotics, bariatric surgery, and gut microbiota transplantation. Diet (e.g., hypocaloric, low-fat, high-protein, and high-fiber diets) can increase the richness of gut microbiome and decrease the Firmicutes to Bacteroidetes phyla ratio and promote weight loss. Prebiotics (e.g., oligofructose-enriched inulin) and probiotics (e.g., fermented milk containing Lactobacillus gasseri species), by modulating gut microbiome, can manage weight gain and obesity. Bariatric surgery causes significant favorable changes in gut microbiome independently of body weight and further enhances weight loss. Clinical data on fecal microbiota transplantation in obesity are relatively limited but promising (Table 11) [18].

Table 11: Tools used for gut microbiome modulation in the management of obesity. Table modified from Heshmati HM (18).

The cost of gut microbiome modulation in the management of obesity is reported in Table 12.

Table 12: Average cost (without insurance coverage) of tools used for gut microbiome modulation in the management of obesity in the USA. Table modified from Heshmati HM (18).

Body Contouring

The remodeling of the body contour is achievable through several invasive or noninvasive methods. Liposuction is the most popular cosmetic procedure in the world and is considered safe for remodeling the body contour [19-22]. It is mainly used for the correction of deep and superficial fat accumulations. Small incisions are performed in different places depending on the area that needs treatment. A cannula is inserted, and the adipose tissue is broken loose from the fibrous stroma with multiple crisscross movements and removed (Figure 10). When properly performed, complications of liposuction are rare. To improve aesthetic results, excision surgery may be necessary for removing the excess skin.

Figure 10: Liposuction remodels the body contour by correcting deep and superficial fat accumulations. Copyright alexonline (ALESSANDRO INNAMORATI)/Depositphotos Inc.

The liposuction technique developed rapidly since the 1970s. After the traditional liposuction technique (suction-assisted liposuction), several adjunct technologies have been developed using ultrasound, power, laser, water, and radiofrequency [19]. Cryolipolysis is also a promising safe and efficient noninvasive technology for body contouring [31]. All these methods differ from each other by their mechanism of action, their response rate, their side effects, and the number of treatments required.

Bariatric Surgery

Bariatric surgery is an established and effective treatment for morbid obesity. It is indicated in subjects with a BMI of at least 40 kg/m ² or a BMI of at least 35 kg/m² in the presence of at least one comorbidity (e.g., type 2 diabetes). Bariatric surgery procedure can be restrictive (e.g., sleeve gastrectomy), malabsorptive (e.g., intestinal bypass), or mixed (e.g., Roux-en-Y gastric bypass) [6,23,24]. The most common bariatric surgery procedures in the USA are sleeve gastrectomy and Roux-en-Y gastric bypass. With sleeve gastrectomy, a staple line is placed along the greater curvature of the stomach and there is a removal of approximately 80% of the lateral aspect of the stomach in a vertical fashion. With Roux-en-Y gastric bypass, a small stomach pouch is created in the upper stomach, the jejunum is divided, and the middle part of it (the Roux limb) is connected to the stomach pouch.

Bariatric surgery induces significant weight loss (at least 20%) and dramatically reduces the comorbidities of obesity (e.g., prediabetes, type 2 diabetes, dyslipidemia, and hypertension) while having a low mortality rate (less than 1%) [23,24]. Roux-en-Y gastric bypass is associated with the largest sustained weight loss. Also, through multiple mechanisms (e.g., reduced caloric intake, reduced gastric emptying, alterations in gastric acid production and bile acids, modifications of gut hormones, and malabsorption), bariatric surgery produces long-term alterations of gut microbiome (e.g., gene richness and composition) independently of body weight (Figure 11) [32]. These changes counteract those observed in obesity and can further affect body weight regulation by enhancing weight loss.

Figure 11: Roux-en-Y gastric bypass causes significant changes in the gut microbiome (e.g., gene richness and composition), further enhancing weight loss. Copyright Sakurra (Viktoriia Kasianiuk)/ Depositphotos Inc.

The relevant or common adverse effects of body contouring and bariatric surgery are reported in Table 13.

Table 13: Relevant or common adverse effects of body contouring and bariatric surgery in alphabetical order (non-exhaustive list).

The costs of body contouring and bariatric surgery are reported in Table 14.

Table 14: Average cost (without insurance coverage) of body contouring and bariatric surgery in the USA.

In the USA, less than 1% of subjects with obesity who are eligible for bariatric surgery benefits from it. The reasons for this undertreatment rate are mainly related to adverse effects and cost of bariatric surgery.

Special Populations

Special populations impacted by excess adiposity include children and adolescents, elderly subjects, pregnant women, and subjects with type 2 diabetes (non-exhaustive list).

Children and Adolescents

Pediatric obesity is a serious public health issue that will challenge health providers for many years to come [33-36]. The worldwide number of children and adolescents with obesity is approximately 100 million (Figure 12). The prevalence of pediatric obesity in the USA is around 19%. The risk of adult obesity is at least 2 times greater for children with obesity than for children without obesity. The associated comorbidities in youth with obesity (e.g., prediabetes, type 2 diabetes, dyslipidemia, and hypertension) can impact the adulthood health and longevity.

Figure 12: Pediatric obesity is becoming a major health challenge worldwide. Copyright agnieszka (Agnieszka Terenowska)/ Depositphotos Inc.

In addition to preventive measures, pediatric obesity can be managed with multidisciplinary approaches including lifestyle (diet, exercise, and behavioral change), drugs (e.g., Xenical^®, Adipex-P^®, and Saxenda^®), and bariatric surgery [33-36].

However, lifestyle interventions should be the first-line therapy in the management of pediatric obesity.

Elderly Subjects

Over the last several decades, there has been a dramatic expansion of the elderly population. By the year 2030, at least 20% of the population of the USA will be aged 65 years or older. Geriatric obesity is a growing global health concern. In the USA, the prevalence of geriatric obesity using BMI criteria parallels the prevalence of non-geriatric obesity (> 33%) [10]. Interestingly, centenarians have a lower prevalence of overweight and obesity [37]. Geriatric obesity can cause impaired physical function, decreased quality of life, several comorbidities, institutionalization, and ultimately death [10,38].

Weight loss intervention in older subjects is a controversial topic [10,38]. Several studies have shown that increased adiposity may have a protective effect in older adults. Due to the high prevalence of sarcopenia in old subjects, BMI is not a reliable marker for the management of obesity as it may not accurately reflect the adipose tissue mass. In several cases, because of the potential risk for aggravation of sarcopenia and osteopenia, weight maintenance rather that weight loss may be the most prudent approach (Figure 13).

Figure 13: The management of obesity in the elderly population is a new medical challenge. Copyright ponytail1414 (Leslie Murray)/ Depositphotos Inc.

Pregnant Women

Obesity during pregnancy is a growing health problem worldwide. In Western countries, the prevalence of obesity in pregnant women is around 30% (Figure 14). Obesity can increase maternal, fetal, and neonatal risks (e.g., gestational diabetes, gestational hypertension, preeclampsia, congenital defects, preterm birth, and stillbirth) [39-41]. Chronic fetal hypoxia is a potential contributing factor [42]. Maternal obesity can also cause major cardiovascular events later in life [39]. Epigenetic alterations may be responsible for this outcome [41].

Figure 14: Approximately 30% of pregnant women in Western countries have obesity. Copyright Morphart (Patrick Guénette)/ Depositphotos Inc.

Pregnancy in women with obesity should be considered and managed as a high-risk condition. Weight loss before pregnancy is the most effective way to reduce maternal and fetal risks.

Subjects with Type 2 Diabetes

Type 2 diabetes is a global pandemic [43]. In the USA, the numbers of adult subjects with type 2 diabetes is around 35 million. Type 2 diabetes is closely related to overweight and obesity. Around 30% of subjects with obesity have type 2 diabetes. Among subjects with type 2 diabetes, at least 85% have overweight or obesity.

Weight loss is an important objective in the treatment of most subjects with type 2 diabetes. However, weight loss in these individuals has usually been a challenge [44]. Fasting plasma glucose and several antidiabetic drugs can impact body weight and the efficacy of weight-loss programs (Figure 15). If subjects are on hypocaloric diet alone, as glycemic control improves, urinary glucose decreases or disappears leading to a reduction of weight loss or a weight gain. The weight loss in these subjects usually reaches a plateau after 6 months [44]. Antidiabetic drugs can either promote weight loss (e.g., biguanides and glucagon-like peptide-1 agonists), be weight neutral (e.g., alpha-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors), or cause weight gain (e.g., insulin and sulfonylureas). When combined with lifestyle changes in a weight-loss program, antidiabetic drugs can either potentiate or antagonize weight loss. The weight loss and weight gain caused by these drugs usually occur within the first year of treatment. The extent of weight change can be up to approximately 4 to 5 kg for either weight loss or weight gain [45]. Treatment decision for the use of antidiabetic drugs should give priority to weight-friendly strategies.

Figure 15: The efficacy of weight-loss programs can be impacted by fasting plasma glucose and antidiabetic drugs. Copyright grib_ nick (Andrii Kovalenko)/Depositphotos Inc.

Deficient Adiposity

Lipodystrophies are examples of deficient adiposity. They are heterogeneous disorders characterized by selective loss of body fat and predisposition to insulin resistance. They can be genetic (e.g., Berardinelli-Seip syndrome and mandibuloacral dysplasiaassociated lipodystrophy) or acquired (e.g., Lawrence syndrome and Barraquer-Simons syndrome), partial or generalized [46,47].

Conclusion

Excess adiposity is the expansion of adipose tissue leading to overweight/obesity. Obesity is a major health problem worldwide causing multiple comorbidities, high mortality, and high cost for the society. Management of excess adiposity requires multidisciplinary approaches including lifestyle (e.g., diet, exercise, and behavioral change), food supplements, drugs, medical devices, gut microbiome modulation, body contouring, and bariatric surgery. Long-term weight maintenance is a challenging goal for most patients and physicians.

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