The pathophysiology of visceral adipose tissues in cardiometabolic diseases

Abstract

Central pattern of fat distribution, especially fat accumulation within the intraabdominal cavity increases risks for cardiometabolic diseases. Portal hypothesis combined with a pathological remodeling in visceral fat is considered the major etiological factor explaining the independent contribution of visceral obesity to cardiometabolic diseases. Excessive remodeling in visceral fat during development of obesity leads to dysfunctions in the depot, characterized by hypertrophy and death of adipocytes, hypoxia, inflammation, and fibrosis. Dysfunctional visceral fat secretes elevated levels of fatty acids, glycerol, and proinflammatory and profibrotic cytokines into the portal vein directly impacting the liver, the central regulator of systemic metabolism. These metabolic and endocrine products induce ectopic fat accumulation, insulin resistance, inflammation, and fibrosis in the liver, which in turn causes or exacerbates systemic metabolic derangements. Elucidation of underlying mechanisms that lead to the pathological remodeling and higher degree of dysfunctions in visceral adipose tissue is therefore, critical for the development of therapeutics to prevent deleterious sequelae in obesity. We review depot differences in metabolic and endocrine properties and expendabilities as well as underlying mechanisms that contribute to the pathophysiological aspects of visceral adiposity in cardiometabolic diseases. We also discuss impacts of different weight loss interventions on visceral adiposity and cardiometabolic diseases.

1. Introduction

Obesity has rapidly increased over the past several decades, doubling in more than 70 countries from 1980 to 2015 (1). People with obesity are at higher risks of developing insulin resistance (IR), beta-cell dysfunction, type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular diseases (CVD), several types of cancer, and disability (2). Furthermore, obesity is positively associated with all-cause mortality, especially in adults younger than 65 years (2). Obesity poses a substantial economic burden in society. The estimated medical cost of obesity in the US was nearly $173 billion 2019 dollars and it is expected to increase further across countries regardless of economic and geographical context (3). Therefore, there is utmost public interest in developing strategies to prevent or treat obesity and its associated diseases.

Obesity is defined as excess accumulation of fat mass and adipose tissues (ATs) are the main storage sites of fat in humans. ATs play critical roles in systemic health by functioning as metabolic, endocrine, and immune organs and higher mass of dysfunctional AT in obesity is considered a major pathological factor for its associated diseases (4). ATs are distributed throughout an organism and depending on the locations, their impacts on cardiometabolic disease risks differ such that fat accumulation in the lower-body subcutaneous is more favorable, while the upper-body fat accumulation, especially within the intraabdominal cavity, has deleterious effects on cardiometabolic diseases (5–7).

Several hypotheses have examined the independent contribution of visceral adiposity to cardiometabolic diseases. Visceral fat is a maker of ectopic fat deposition, accumulation of fat in or around organs that impairs functions of the affected organs increasing disease risks (8). Additionally, visceral fat becomes more dysfunctional during development of obesity (4) secreting high levels of deleterious metabolic and endocrine products into the portal vein directly impacting the liver, the primary regulator of systemic metabolic health (9). We review current literature and provide perspectives on depot differences in adipose functions and remodeling capacities to understand the pathophysiological aspects of visceral obesity in cardiometabolic diseases. We also compare different lifestyle interventions for obesity in their impacts on visceral adiposity and improvement in cardiometabolic diseases.

2. Adipose tissues are present in multiple locations in the body

ATs are distributed throughout an organism as specific and discrete fat depots with each exhibiting distinctive characteristics in developmental origin, morphology, metabolism, endocrine activity, immune response, and remodeling capacity. ATs are first divided into subcutaneous and visceral fat. Subcutaneous ATs (SATs) lie underneath the skin and provide mechanical and immune protection as well as insulation. SATs are divided into the upper-body abdominal and the lower-body gluteofemoral fat in humans (10). Visceral fat is associated with the internal organs and includes omental, mesenteric, and epiploic fat depots in humans. The omentum hangs off from the stomach down into the abdomen covering the intraperitoneal organs, mesenteric fat is attached to the small intestine, and epiploic fat is associated with the colon (2). Other intraabdominal depots are the retroperitoneal fat that lies at the back of the abdominal cavity and the perirenal fat that surrounds the kidneys. Beyond these, there are other smaller adipose depots, including epicardial and pericardial fat (11).

In rodents, the major intraabdominal depots are periovarian/parametrial fat in females and perigonadal/epididymal fat in males (12). Although it is not anatomically connected to the digestive organs and does not drain to the portal vein, epididymal fat shares similarities to human omentum in its transcriptome and remodeling capacities (13;14). The perigonadal fat also functions a barrier that filters gut-derived endotoxins, similar to visceral depots in humans (15). Therefore, epididymal fat is frequently used as a model of visceral AT (VAT). Small amount of true visceral depots, mesenteric and omental fat, along with other intraabdominal fat, retroperitoneal and perirenal AT, also exist in rodents (12). The two major subcutaneous depots in rodents are the anterior (dorsal) and posterior (inguinal) fat and the latter is often studied as a model of SAT.

In addition to white fat, thermogenically more active brown fat and inducible form of brown-like adipocytes within white depots exist and their amount is reported to be reduced in obesity and metabolic diseases (16). Brown and brown-like adipocytes contain higher mitochondrial density and express uncoupling protein 1, through which energy can be dissipated as heat (17). They take up glucose and lipids from the circulation and oxidize them to generate heat and therefore, enhancing the amount and activity of brown and brown-like adipocytes improves systemic glucose and lipid metabolism providing protection against obesity-associated diseases (18;19). Although inguinal subcutaneous fat in rodents is more prone to be browned (20), human omental and subcutaneous depots similarly obtain brown-like adipocytes (21;22). Further, expression levels of uncoupling protein 1 are higher in omental than subcutaneous fat (21). These data indicate species-dependent depot differences in browning capacity. Additionally, they suggest that depot differences in browning capacity is not a major factor that explains the pathological aspects of visceral fat in cardiometabolic diseases in humans.

3. Visceral adiposity is an independent risk factor for cardiometabolic diseases

Albeit being a minor depot representing 5–10% of total fat in women and 10–20% in men (2), visceral fat mass is independently associated with cardiometabolic diseases (5–7). On the contrary, subcutaneous fat accumulation, especially in the lower-body gluteofemoral region, provides protective effects (10). Additionally, adipocyte numbers in subcutaneous, but not in visceral fat, are related to more favorable metabolic phenotypes (23). These results support the role of SAT as a metabolic sink. When the expandability of SAT reaches a limit, fat spills over to VAT and other tissues negatively impacting the affected organs. In this sense, VAT can be considered an ectopic fat depot (8).

Women have more body fat containing 25–30% of body weight compared to 10–20% in men. However, women deposit fat in the lower-body SAT and contain less VAT, while men accumulate fat in the central regions, both in omental and abdominal subcutaneous depots (24). Additionally, women have greater amount of brown and brown-like adipocytes than men (25). These sexual dimorphisms in fat distribution pattern are proposed to explain the lower risks of cardiometabolic diseases in females, especially before menopause (26). While underlying mechanisms are not fully uncovered, sex steroid hormones and sex chromosomes are important regulators that govern sexual dimorphisms in total fatness and fat distribution patterns (10).

3.1. Quantification of visceral fat mass

Body mass index (BMI), calculated as a person’s weight divided by the square of his height (kg/m²), is a simple index that is commonly used to classify overweight and obesity in adults. Although BMI highly correlates with percent fat mass across population, it is not a good estimate for fat distribution pattern due to variations by sex, age, and race/ethnicity (27). 2- to 3-fold variations in visceral fat mass have been reported, and using BMI as a predictor of visceral adiposity could misclassify certain populations (27). Additionally, individuals with low amount of VAT within overweight and obese categories have more favorable metabolic profiles and sometimes referred as metabolically healthy obesity (28). Accurate quantification of VAT mass is therefore, important for the early detection and application of preventive or therapeutic interventions for cardiometabolic diseases.

The emergence of imaging techniques, computed tomography (CT) and magnetic resonance imaging (MRI), has greatly advanced our understanding of body composition and its relationship with disease risks. With these imaging technics, it is possible to detect or estimate VAT as well as fat content in or around organs that is more closely associated with cardiometabolic diseases (29). A single axial image of the abdominal region usually at the level of the L4–5 vertebral disc is processed for the quantification of VAT area and volumetric VAT mass can be calculated using multiple slices of images (30;31). Normative VAT mass values for different populations have been proposed (32–34).

Limitations of VAT measurement with CT or MRI include exposure to radiation, cost, accessibility, and time-consuming manual processing of images, and software to estimate VAT mass with dual X-ray absorptiometry (DXA) has been developed. DXA exposes subjects to less radiation than CT and provides additional body composition data, including percent body fat with minimal additional time. Studies reported high correlations between the VAT mass measured with CT or MRI and DXA-estimated VAT mass in adults (30;31;35). However, limitations in DXA-estimated VAT have been reported such as significant proportional bias in children and older male subjects and inability to accurately track longitudinal changes in visceral fat mass (30;31).

3.2. Indicators of visceral adiposity for cardiometabolic disease risks

Quantification of VAT mass with CT, MRI, or DXA is not always feasible or realistic in practice and surrogate anthropometric measures provide convenient clinical indicators. Among anthropometric measures, waist circumference (WC) is considered a simple indicator of central fat distribution pattern providing additional information to BMI (36). Larger WC is strongly associated with cardiometabolic diseases independent of overall adiposity (37–39). Further, WC is reported to be more sensitive to lifestyle changes than BMI and reduction in WC can suggest favorable changes in visceral fat (40;41). Recently, the International Atherosclerosis Society and the International Chair on Cardiometabolic Risk have jointly proposed sex- and BMI category-specific WC thresholds based on ethnicity (41).

Other surrogate measures include waist-hip ratio (WHR) and waist-height ratio (WHtR). Studies have shown that WC compared to WHR is more strongly associated with DXA-estimated VAT mass, while WHtR is the best predictor among the three indicators (32;34). Further, WHtR was a better screening tool than WC and BMI for cardiometabolic disease risk factors (42). These demonstrate the usefulness of WHtR in practice and 0.59 has been suggested as a WHtR cut-point for predicting visceral obesity in both sexes (32).

Several calculated indexes of visceral fat functions have been developed to predict cardiometabolic disease risks. Visceral Adiposity Index, a sex-specific calculated index using WC, BMI, and serum levels of triacylglycerol (TAG) and high-density lipoprotein (43), is positively associated with IR, blood pressure, and other cardiometabolic variables (44;45). Metabolic Score for Visceral Fat that combines noninsulin-based metabolic score for IR index (calculated using serum levels of glucose, TAG, and high-density lipoprotein) with BMI, WHR, age, and sex, is also used (46).

4. Depot differences in adipose cellularity

ATs are composed of multiple cell types and adipocytes are the parenchymal cells occupying the majority of the tissue volume. Adipocytes are characterized by the large central lipid droplet that takes up over 90% of the cell volume. Adipocyte sizes range from 10 to 150 μm or 100 to 1200 pL in humans and average fat cell size highly correlates with BMI and total fat mass (47). Other cell types, including adipose progenitors (APs), various immune cells, fibroblasts, and endothelial cells are present within the stroma and the numbers of stromal cells are reported to be 2 to 4 times greater than adipocytes (48).

Mean adipocyte sizes are smaller in omental than abdominal subcutaneous fat in women, while they are similar between the two depots in women with severe obesity and men (2). Other depot differences include higher vascularization and total number of stromal cells per unit mass in VAT (48;49). In both sexes of rodents, mean fat cell sizes are greater in intraabdominal ATs that are the major adipose fat depots (50). These depot differences in adipose cellularity contribute to heterogeneities in their metabolic and endocrine functions as well as remodeling capacities.

5. Depot differences in adipose functions

As metabolically active endocrine organs, ATs regulate systemic health. Depot differences in adipose metabolic and endocrine functions are discussed as they explain regional fat distribution pattern as well as the independent contribution of visceral adiposity to cardiometabolic diseases.

5.1. Heterogeneities in adipose metabolic functions

ATs are highly plastic expanding or contracting depending on systemic energy status. Adipocytes store energy in lipid droplets that consist of neutral lipid core enveloped in a phospholipid monolayer with associated proteins (51). In post-prandial condition, insulin increases energy storage by suppressing intracellular lipolysis and stimulating TAG synthesis (52). When systemic energy demands increase during fasting or exercise, lipolysis is stimulated and fatty acids (FAs) and glycerol are released from adipocytes (53). Moderate levels of weight gain or loss occur without significant changes in numbers of adipocytes (47), indicating that fat depot mass is mainly regulated by the balance between TAG synthesis and breakdown.

5.1.1. Glucose uptake

Glycerol backbone in TAG is mostly derived from glucose uptake and metabolism into glycerol-3-phosphate. Glucose uptake per adipocyte is lower in omental than abdominal subcutaneous fat in women, while it is similar between the two depots in men (54;55). However, when expressed per unit fat mass, glucose uptake is greater in omental than abdominal subcutaneous fat (56;57). These seemingly contradictory findings can be explained by the fact that adipocyte size is smaller and hence, the omentum contains more adipocytes per unit mass in women (58). Lower glucose uptake per adipocyte in female omentum may explain the lower visceral fat mass in women than men.

5.1.2. De novo lipogenesis (DNL)

DNL is a complex process through which FAs are synthesized from non-lipid precursors and incorporated into TAG. Multiple enzymes including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FASN) catalyze DNL (59). In obesity, hepatic DNL is induced and contribute to systemic insulin resistance (60). However, adipose DNL is suppressed in obesity and restoring DNL in AT ameliorates obesity-induced insulin resistance (61). Adipose DNL is important for the production of a novel family of lipids including palmitoleate and FA esters of hydroxy-FAs that exerts insulin-sensitizing and antiinflammatory actions (62). These support regulatory functions of adipose DNL in systemic metabolism.

A recent proteomic profiling showed that protein levels of ACLY, ACC, and FASN are higher in visceral than subcutaneous fat, indicating higher capacity for DNL in the former depot (63). Further, expression levels of ACC and FASN are reduced in subcutaneous fat in obesity, while their levels in visceral fat are similar between lean and obese individuals (64),, suggesting depot-specific suppression of DNL in SAT. Whether DNL differ between visceral and subcutaneous fat contributing to the pathophysiological aspects of visceral fat in obesity remains to be determined.

5.1.2. FA uptake

Although adipose DNL is induced upon feeding high carbohydrate diets, DNL is a not a major component in TAG in AT of adult humans who are consuming typical western diets (65) and FAs used for TAG esterification are mostly derived from lipoprotein lipase (LPL)-mediated hydrolysis of neutral lipids in TAG-rich lipoproteins or direct FAs uptake from the circulation. LPL activity per adipocyte is lower in omental than abdominal subcutaneous fat in women across ranges of adiposity and fat distribution pattern (66;67). In contrast, in males with intermediate levels of BMI or WC, LPL activity is higher in omental than abdominal subcutaneous fat (68).

In vivo meal FA uptake and direct FA uptake from the circulation per unit fat mass are greater in omental than subcutaneous fat in both sexes (58;69-71). Sex-differences in FA uptake have been also reported such that majority of FAs is uptaken into subcutaneous fat in females, while a significant portion is taken into visceral fat in males (72). Therefore, lower levels of direct FA uptake along with LPL-mediated hydrolysis of neutral lipid in TAG-rich lipoproteins and subsequent FA uptake in female omental depot contribute to the sexual dimorphisms in visceral adiposity.

5.1.3. Lipolysis

Omental compared to subcutaneous adipocytes exhibit lower or similar basal lipolytic rates, but higher incremental (as percent delta over baseline) responses to mixed or beta-adrenergic agonists ex vivo (67;73-76). Additionally, omental adipocytes are less sensitive to the anti-lipolytic actions of insulin (77). Several factors, including lower levels of anti-lipolytic alpha-2 adrenergic receptor (78;79) and differential expression levels of lipid droplet-associated proteins and lipases could potentially contribute to the depot differences in the lipolytic rates (80;81). Higher blood flow to visceral fat (57) as well as sympathetic innervation of VAT also contribute to the more enhanced lipolysis in VAT under stimulated conditions in vivo (82). Elevated levels of viscerally derived non-esterified FAs (NEFAs) and glycerol especially in individuals with visceral obesity (83) directly affect hepatic functions.

The contribution of splanchnic NEFAs to systemic levels is estimated to be ~6% in lean and ~13% in obese individuals (84;85), indicating that VAT is not a significant source of NEFAs to the periphery. Lipolysis is higher in the upper-body than lower-body subcutaneous fat and ~70% of systemic rates of NEFA appearance are contributed by the upper-body subcutaneous fat in humans in vivo (84;85). Higher levels of FAs derived from the upper-body fat contribute to systemic metabolic derangement by impairing insulin signaling pathways in the skeletal muscle as well as the liver, partially explaining the association between central adiposity and cardiometabolic diseases.

5.2. Depot differences in adipose endocrine functions

ATs secrete myriads of peptide hormones and cytokines. Other bioactive molecules, including various lipid species, glucocorticoids, and sex steroid hormones, are also either synthesized de novo or converted into active forms in ATs (86). These endocrine products regulate adipose biology as well as systemic functions. While leptin, adiponectin, and serum amyloid A are produced by adipocytes, proinflammatory cytokines such as tumor necrosis factor-alpha (TNFα) and interleukins (ILs) are secreted by stromal cells.

Omental than subcutaneous fat secretes lower levels of leptin, while they produce comparable levels of adiponectin and serum amyloid A (87;88). Secretion of proinflammatory cytokines, IL-6, IL-8, macrophage chemoattract protein-1, retinol binding protein, and TNFα, is higher in omental fat, and these depot differences are amplified in obesity (88;89). These viscerally derived cytokines are secreted into the portal vein directly bathing the liver. Omentin, an insulin sensitizing and antiinflammatory adipokine, is more abundantly expressed in the visceral fat (90) and has potential to improve hepatic function. However, recent meta-analyses reported inconsistent findings between omentin levels and hepatic fat (91;92) and its effects on hepatic functions remains to be determined.

5.3. Factors that contribute to depot differences in adipose functions

Depot-specific activation of cortisol from cortisone, expression levels of glucocorticoid receptors, and glucocorticoid-regulation of adipose gene expression also explain depot-differences in adipose functions (93). Proinflammatory and profibrotic cytokines are produced from stromal cells and therefore, heterogeneities in cellular compositions between depots explains their higher secretion from visceral fat (48). Moreover, elevated immune cell infiltrations into visceral fat of obesity contribute to the exaggerated depot differences in proinflammatory cytokine expression (88;89). Additional factors include sex steroid hormones and sex chromosomes that also contribute to sex-dependent depot differences in adipose functions (10). Recent studies in mice indicate cell-autonomous intrinsic differences at the level of APs and adipocytes between adipose depots (94). Heterogeneities in APs also contribute to the higher secretion of proinflammatory and profibrotic cytokines from visceral fat, as discussed later. However, whether a specific population of adipocytes derived from an AP subtype are functionally distinctive and how they contribute to the unique characteristics between depots, potentially sex-dependent manners, are not fully elucidated.

6. VAT becomes more dysfunctional during development of obesity

Dysfunctional AT exhibits a group of interrelated complications, chronic inflammation, fibrosis, and hypoxia, that is considered a major etiological factor of cardiometabolic diseases in obesity (95). To cope with excess demands of energy storage during chronic overnutrition, adipocytes become hypertrophied that leads to death of adipocytes. Further, angiogenesis does not occur fast enough to supply oxygen and hence, hypoxia occurs in the AT of obesity. These events recruit proinflammatory immune cells to the tissue and activated macrophages further increases tissue inflammation and fibrosis.

During development of obesity, epidydimal fat in mice and omental depot in humans become more dysfunctional exhibiting higher levels of crown-like structures (defined by dead adipocytes surrounded by macrophages), inflammation, and fibrosis (50;96-100). These in turn cause alterations in metabolic and endocrine products released from VAT into the portal vein. Exposure to high levels of FAs and glycerol causes hepatic fat accumulation and increases the production of very low-density lipoprotein and glucose from the liver (Figure 1). Additionally, proinflammatory and profibrotic cytokines induce IR, inflammation, and fibrosis in the liver. Combined, these lead to systemic metabolic disturbances, including hyperlipidemia, hyperglycemia, and IR. Of note, intraabdominal depots in females become less dysfunctional in response to diet-induced obesity (DIO) (50;101) or during normal aging (102). This explains, at least in part, the lower risk of cardiometabolic diseases in females.

Figure 1. The pathological aspects of visceral fat in cardiometabolic diseases.

Visceral adipose tissue becomes more dysfunctional and secretes high levels of metabolic products [fatty acids (FAs) and glycerol] and proinflammatory and profibrotic cytokines (tumor-necrosis factor-alpha, interleukin-6 and −8, tumor growth factor-beta) into the portal vein directly bathing the liver. These factors induce fat accumulation, insulin resistance, inflammation and fibrosis and increase production of glucose and very low-density lipoprotein (VLDL) in the liver, which in turn leading to hyperglycemia, hypertriglyceridemia, and systemic inflammation increasing risks of cardiometabolic diseases. Metabolic and endocrine products derived from subcutaneous fat, especially from the upper-body depot, enter the systemic circulation before reaching the liver and negatively impact skeletal muscle and other organs (not shown).

6.1. Depot differences in adipose remodeling capacity and dysfunctions

ATs remodel through hypertrophy and/or hyperplasia and hyperplastic expansion through recruitment of APs and their differentiation into adipocytes is considered a healthier expansion (103). Gene expression profiles of adipogenic transcription factors suggest that hyperplasia is predominant in subcutaneous depot while both omental and subcutaneous depots expand through hypertrophy in humans (104). Consistent with this, adipose stromal cells or APs isolated from the visceral depot exhibit lower adipogenic capacity in vitro (14;48;105). They secrete higher levels of antiadipogenic factors, including TNFα and tumor growth factor-beta (TGFβ) ligands (100;106), indicating a cell-autonomous poor hyperplasic expansion in VAT. TNFα induces a macrophage-like phenotype (107) and TGFβ ligands induce a myofibroblast phenotype in APs (108). Therefore, they may further exacerbate inflammation and fibrosis in VAT.

Recent in vivo lineage tracing studies in mice, however, showed that in response to DIO, inguinal subcutaneous fat expands mainly through hypertrophy while intraabdominal depot grows through both hypertrophy and hyperplasia (109;110). Similarly, we also showed that adipocyte sizes are smaller in inguinal depot and high-fat diet (HFD) increases the depot weight mainly through hypertrophy in both sexes (50). Sex-dependent depot differences in adipose expandability in responses to HFD have been reported. In female mice, HFD induces hyperplasia in both parametrial and inguinal depots, while in male mice, HFD induces hyperplasia in gonadal, but not in inguinal fat (111). In contrast, we found that HFD increases perigonadal weight by adipocyte hypertrophy and hyperplasia in females, but hypertrophy alone in males (50).

6.2. Factors contributing to depot differences in adipose remodeling capacity and dysfunctions

Depot-specific microenvironments/niches have been shown to contribute to higher hyperplastic growth in epididymal than inguinal fat in mice (111). Higher expression levels of angiogenic factors (112) and depot-dependent regulation of glucocorticoid activation (113) also contribute to hyperplastic expandability in visceral depot in response to energy excess. In addition, in humans, but not in rodents, glucocorticoid induction of LIM domain only 3 enhances adipogenesis in visceral fat (114). In contrast, we found that glucocorticoid-suppression of antiadipogenic TGFβ signaling is impaired in adipose stromal cells derived from human omental fat contributing to their poor adipogenesis in vitro (100). Further studies are warranted for the full understanding of depot specific adipogenesis and remodeling capacity and their underlying mechanisms, especially in humans.

Recent studies in mice posit that heterogeneities in AP subpopulations contribute to dysfunctions in intraabdominal fat. Epididymal fat contains a subpopulation of unique APs that are antiadipogenic, proinflammatory, and fibrogenic while APs in inguinal depot are more or less committed to adipogenesis (115;116). Further, in response to DIO, they proliferate and accumulate in epididymal, but not in inguinal fat (50;116;117). These antiadipogenic APs exhibit a myofibroblast phenotype and secrete factors that inhibit adipogenesis (115). Similarly, we reported that human omental than subcutaneous fat contains more APs with low adipogenic potential (100). Our study also showed that elevated TGFβ signaling in APs contributes to their poor adipogenic capacity and tissue fibrosis in human omental fat (100). TGFβ signaling activity is known to increase proliferation of APs (108) and therefore, high TGFβ may also lead to accumulation of antiadipogenic and profibrotic APs in visceral fat of obesity. Future studies identifying and comparing AP subpopulations between visceral and subcutaneous depots in humans are warranted. Additionally, studies examining how heterogeneities in AP populations contribute to the pathological remodeling in visceral fat in human obesity are also needed.

7. Lifestyle interventions to reduce visceral fat and cardiometabolic diseases

Number of pharmacological therapeutics for weight loss are available and some of them preferentially reduce visceral fat with improvement in CVD (118). However, prescription of those drugs is limited and lifestyle interventions, including caloric restriction (CR) and physical activity (PA) effectively decrease body weight (119). Studies have reported variations in loss between fat depots in responses to different lifestyle interventions and considering the independent effects of visceral and ectopic fat on cardiometabolic diseases, reduction or normalization of VAT and ectopic fat needs to be prioritized over loss in body weight.

7.1. Diet or dietary factors

Numerous randomized clinical trials reported that low carbohydrate (LC) is more effective than low fat (LF) diet in reducing weight, especially during short-to-intermediate periods (120), although no differences (121) or contradictory results have been also reported (122).LC diet more effectively reduces visceral and ectopic fat as well as risk factors for cardiometabolic diseases (121;122). Although recent short-term inpatient clinical studies showed that LF compared to LC diet more effectively decreases fat mass (123;124), their impacts on VAT remains to be examined. As expected, more severe CR has greater effects (125;126). The CENTRAL MRI trial found that the Mediterranean diet, rich in unsaturated fats and low in carbohydrates, is better than LC diet in decreasing ectopic fat in the liver, heart, and pancreas (127). The trial also showed that reduction in visceral and hepatic fat is mainly associated with improvement in lipid profile while superficial SAT loss has minimal effects (127). Other dietary interventions such as high protein or time-restricted feeding also effectively reduce visceral and ectopic fat with favorable metabolic outcomes (128;129).

7.2. Preferential loss of visceral and ectopic fat with aerobic exercise

Numerous studies showed that CR is more effective than PA in reducing weight (130;131). However, an increase in both lean body mass and plasma volume during exercise training may counteract the declines in fat mass contributing to the lower magnitude of weight loss (132). Accordingly, meta-analyses found that exercise training reduces VAT even in the absence of weight loss, while CR does not (132;133). Although 150 min/wk of moderate-intensity PA may decrease VAT, high-intensity training is more effective (134) and aerobic than resistance training is also more effective (135). As expected, combined interventions of CR and PA have greater effects on reducing VAT than each (127;136). PA interventions also decrease ectopic fat (127). Reduction in visceral and ectopic fat with exercise training contributes to its health benefits, including improvement in glucose-insulin tolerance and lipid profiles (137).

7.3. Why VAT is preferentially mobilized during LC diet and exercise?

VAT loss occurs even in the absence of weight loss during exercise training (132;133). It is estimated that 5–10% weight loss is associated with 25–30% reduction in VAT (138). These indicate a greater mobilization of TAG from VAT during negative energy balance. The preferential loss of TAG in VAT could be explained by its higher responses to adrenergically stimulated lipolysis that is further amplified by reduced insulin levels during LC or improved insulin sensitivity with exercise (67;73-75). Lower sensitivity of omental than subcutaneous adipocytes in insulin-suppression of lipolysis (77) may also contribute to the preferential loss of VAT during LC diet.

Conclusions

Heterogeneities in developmental origins, metabolic and endocrine functions, and remodeling capacities explain fat distribution pattern as well as the independent contribution of visceral adiposity to cardiometabolic diseases. Several hypotheses have examined the independent contribution of visceral fat. When the storage capacity in SATs reaches its limit, fat spills over into the intraabdominal depots and visceral adiposity may be a marker of ectopic fat deposition, the primary etiological factor of cardiometabolic diseases. During development of obesity, a pathological remodeling occurs in visceral fat, which results in secretion of high levels of FAs, glycerol, and proinflammatory cytokines, and low levels of beneficial adipokines into the portal vein directly affecting the liver, the central regulator of systemic metabolism. Uncovering underlying mechanisms that leads to excessive modeling in visceral depot is therefore, critical for the development of therapeutic approaches for cardiometabolic diseases in obesity.

Both cell intrinsic and extrinsic factors contribute to the pathological remodeling and dysfunctions in visceral fat of obesity. Lower adipogenesis in stromal cells and APs isolated from visceral depots posits the hypothesis that poor hyperplastic capacity puts stress on the existing adipocytes and dysfunctions in the visceral depot. However, this has been challenged by in vivo lineage tracing studies in mice that showed intraabdominal depots expands through hyperplasia in response to DIO. While more studies are needed to reconcile these inconsistent findings, several species-specific depot differences, including differences in adipocyte cell sizes and glucocorticoid-regulation of adipogenesis have been reported. Therefore, findings from rodent studies need to be carefully examined for their translational relevance in humans. Recent studies showed that antiadipogenic, proinflammatory, and profibrotic subpopulation of APs accumulate more in visceral depots of mice and humans. They secrete TNFα and TGFβ, which further exacerbates the proinflammatory and profibrotic microenvironments within visceral fat of obesity. Studies characterizing and comparing AP and adipocyte subpopulations in human adipose depots are needed. Considering reported sex-dependent depot differences in remodeling capacities that can explain the lower risks of cardiometabolic diseases in females, further studies uncovering molecular details and mechanisms involved in pathological remodeling of visceral fat in both women and men are also warranted.