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The mechanisms by which dysfunctional adipose tissue simultaneously promote T2DM and CVD, focusing on adipose tissue depot-specific adipokines, inflammatory profiles, and metabolism, will be the focus of this review.

The impact that various T2DM and CVD treatment strategies have on adipose tissue function and body weight also will be discussed. The incidence of type 2 diabetes mellitus T2DM has also risen in parallel to the obesity epidemic, and thus is considered a major co-morbidity associated with obesity 2 , 3.

Furthermore, both obesity and T2DM increase the risk of cardiovascular disease CVD , increasing morbidity and mortality by greater than 2-fold 7 — The distribution of adipose tissue is of great importance with regards to these co-morbidities.

Insulin resistance often occurs when fat accumulates in intra-abdominal depots and is associated with a constellation of CVD risk factors, in what is known as the metabolic syndrome Simply measuring body weight, waist circumference, or calculating BMI does not portray a clear picture of body composition nor fat distribution.

Thus, other indices have become more useful for assessing body fat distribution, such as waist-to-hip ratios, as well as methods for assessing body composition, including anthropometry, dual-energy X-ray absorptiometry DEXA , and computed tomography CT scanning.

In this comprehensive review, the complex and interrelated associations between obesity, diabetes, and CVD will be explored in greater detail.

Adipose tissue can be classified by morphology into white, brown, or beige subsets. Adipose tissue is comprised of many different cell types, which coordinately secrete numerous cytokines, chemokines, and hormones.

Approximately one third of the cells within adipose tissue are adipocytes, with the rest represented by fibroblasts, endothelial cells, macrophages, stromal cells, immune cells, and pre-adipocytes. In most lean, healthy individuals, WAT is confined to defined depots. But in certain conditions such as obesity and lipodystrophy, WAT mass can increase ectopically in areas that may influence the susceptibility to comorbidities such as diabetes and atherosclerosis.

Such ectopic WAT areas are mostly located within the visceral cavity, and include intrahepatic discussed in the section on Ectopic Fat below , epicardial epiWAT, between the heart and the pericardium , perivascular PVAT, surrounding major blood vessels , mesenteric fat MWAT, contiguous with digestive organs in the viscera , omental fat OWAT, an apron of fat that stretches over the intestines, liver, and stomach , and retroperitoneal fat RWAT, surrounding the kidneys.

In addition to WAT depots, brown adipose tissue BAT represents a distinct type of adipose tissue that is characterized by its morphology and function, with concentrated mitochondria giving it a characteristic brown appearance. Beige fat represents a third new classification of adipose tissue, in which brown adipocytes appear within classical WAT depots.

Each of these adipose depots will be discussed in more detail below. Thus, more than any other depot, subcutaneous WAT represents a physiological buffer for excess energy intake during times of limited energy expenditure.

When this storage capacity is exceeded, either due to an inability to generate sufficient new adipocytes limited hyperplasia or an inability to further expand existing adipocytes limited hypertrophy , fat begins to accumulate ectopically in areas outside the subcutaneous WAT see sections on Ectopic and Visceral Fat below.

Additionally, subcutaneous WAT functions as an insulator to prevent heat loss, as a barrier against dermal infection, and as a protective cushion against physical external stress Subcutaneous WAT likely arises from adipocyte precursor cells that are distinct from adipocytes that arise ectopically, for example in visceral fat Elegant work by Kahn et al.

has demonstrated that pre-adipocytes isolated from mouse and human subcutaneous WAT expresses developmental genes that are present prior to the development of WAT in a pattern that is maintained throughout adulthood, suggesting a cell-autonomous function Thus, WAT distribution has a strong heritable component The beneficial effects of subcutaneous WAT to glucose metabolism have been demonstrated in numerous ways.

Epicardial adipocytes share embryonic origins with mesenteric and omental adipocytes epiWAT also termed pericardial WAT is in close proximity to the myocardium, enabling a shared microcirculation between epiWAT and certain areas of the heart Due to its proximity to the heart, epiWAT is thought to be approximately twice as metabolically active as other WAT depots, with higher levels of fatty acid uptake and fatty acid release due to lipolysis As a metabolically active WAT depot, epiWAT secretes several adipokines and vasoactive substances such as adiponectin, resistin, vascular endothelial growth factor VEGF , and inflammatory cytokines and chemokines that impact the adjacent myocardium In fact, due to the complete lack of a fibrous fascial layer between epiWAT and the myocardium, diffusion of fatty acids and other bioactive hormones from epiWAT to myocytes and coronary vessels is easily facilitated Most humans possess a small amount of epiWAT, which provides fatty acids through lipolysis of its triglyceride stores for energy use by the heart.

However, obese humans possess an enlarged epiWAT depot, which is clinically related to features of the metabolic syndrome discussed in later sections. Fat that surrounds blood vessels is termed perivascular fat PVAT. It has now been recognized that PVAT has characteristics that resemble both BAT and WAT, and is considered to be an active participant in vascular homeostasis PVAT produces many bioactive molecules that influence vascular reactivity, including adipokines e.

Thus, PVAT can directly contribute to vascular tone, in addition to playing a supportive role in maintaining vessel structure. It has been suggested that PVAT in the thoracic aorta resembles BAT, while PVAT in the abdominal aorta exhibits properties of both BAT and WAT Thus, if PVAT becomes dysfunctional in the setting of obesity, it can pivot from providing an atheroprotective role to promoting atherosclerosis.

This concept will be evaluated further in later sections. Fat localized within the visceral compartment has been classified as omental, mesenteric, and retroperitoneal.

Lean, healthy individuals do not have large amounts of visceral fat, which largely falls into the category of ectopic fat.

Visceral fat is highly metabolically active and is constantly releasing free fatty acids FFA into the portal circulation. As such, visceral fat content contributes to various features of the metabolic syndrome, such as hyperinsulinemia, systemic inflammation, dyslipidemia, and atherosclerosis 25 , to be discussed in more detail in later sections pertaining to obesity.

BAT is localized to distinct anatomical regions that have been well-characterized in rodents By taking up circulating fatty acids, BAT functions to generate heat by uncoupling chemical energy production ATP via oxidative phosphorylation into heat production non-shivering thermogenesis , thereby contributing to the clearance of plasma triglycerides and the mitigation of ectopic lipid storage While originally believed to be a depot exclusive to hibernating and small mammals, and present to some degree in human infants, adult humans have recently been shown to have functional and inducible levels of BAT that respond to cold and sympathetic nervous system activation 28 — Given the relatively small amount of BAT present in humans, the endocrine potential of batokines is relatively unknown, but it is clear that factors secreted from BAT exert paracrine and autocrine functions.

While the relative BAT mass in humans and rodents is small compared to other adipose depots, its relative contribution to metabolic health may be higher. In rodents and other small mammals, the primary BAT depots are located in the interscapular space and supraclavicular regions, among many others 26 , With prolonged stimulation, i.

BAT recruitment is associated with enhanced proliferation and differentiation of BAT precursor cells. As the name suggests, beige fat has been described as the presence of brown adipocytes within classic WAT depots.

While beige fat shares some features of classical BAT such as systemic triglyceride-lowering, beige fat is thought to be physiologically distinct from BAT, with differential expression of certain genes involved in metabolism, inflammation, and transcription 35 , Moreover, human BAT exhibits similar morphology and function as both rodent BAT and beige tissue 30 , 37 — 39 , complicating comparisons between the two species.

In rodents, subcutaneous WAT is the most susceptible depot to browning, while in humans it is visceral WAT It is generally believed that the majority of WAT depots can develop browning under particular conditions, but more work is needed in this area.

There is a growing list of physiological stressors that can promote the browning of WAT, including cold exposure, exercise, bariatric surgery, cancer cachexia, severe burns, as well as pharmacological and dietary components such as conjugated linoleic acid, short-chain fatty acids, capsaicin, non-caffeinated green tea extract, thiazolidinediones TZDs , and β-adrenergic receptors 41 — There is some debate regarding the origins of beige adipocytes, as well as their impact on energy homeostasis.

This theory suggests that dormant beige adipocytes can become quickly and readily activated when needed, reminiscent of an immune response. Beige adipocytes were initially thought to arise from transdifferentiation from white adipocytes, with the ability to de-differentiate back into white adipocytes 55 , Additional studies in vitro suggest that this is likely not the case The identity of committed beige adipocyte precursors has not been fully elucidated, but there is evidence from isolated WAT stromal cells that beige adipocyte precursors are distinct from white adipocyte precursors 36 , 39 , It has been suggested that strategies that increase the number of beige adipocytes in mouse WAT also protect them from diet-induced obesity 59 — Adipose tissue is an essential organ for the regulation of energy homeostasis.

Primarily tasked with storing excess energy as triglycerides, adipocytes undergo hyperplasia to increase the number of adipocytes and hypertrophy to increase the size of each adipocyte, allowing adipose tissue to expand in times of nutrient excess. As needed, i. Stored triglycerides are therefore in a constant state of flux, whereby energy storage and energy mobilization are determined largely by hormonal fluctuations.

In healthy lean individuals, the majority of adipose tissue resides in subcutaneous depots, where it serves a thermoregulatory function, and from which stored triglycerides can be readily mobilized when needed Conditions that favor adipose tissue expansion, if endured chronically, will eventually exceed the storage capacity of defined adipose tissue depots, leading to the ectopic deposition of triglycerides in other tissues, including intra-abdominal depots discussed in more detail in later sections.

BAT plays an important role in thermoregulation in mammals, including adult humans BAT tissue is rich in mitochondria and uniquely expresses uncoupling protein-1 UCP-1 , which enables heat production by uncoupling ATP synthesis. BAT-mediated thermogenesis has garnered substantial attention recently, as increasing BAT mass or activity could be an effective strategy to combat obesity.

While the primary function of WAT is to manage energy storage, brown adipocytes efficiently burn fatty acids released from WAT during adaptive thermogenesis In addition, beige fat could also contribute to fat catabolism, potentially reducing WAT stores.

Human brown adipogenesis occurs in response to chronic or repeated cold stimulation, or in response to pharmacologic compounds such as beta adrenergic receptor β-AR agonists 68 , However, these browning-inducing methods mediated by the sympathetic nervous system are not practical as a weight loss strategy for several reasons: 1 the browning effects of cold exposure are rapidly reversible, 2 repeated cold exposure is too time- and energy-consuming to be a practical therapeutic, and 3 β-ARs promote adverse cardiometabolic events.

Therefore, mechanisms of WAT browning that are long lasting and act independently from the sympathetic nervous system are highly sought after. A new mechanism of WAT browning that does not involve the sympathetic nervous system SNS has recently been described.

Adipose tissue resident macrophages can secrete norepinephrine NE , the neurotransmitter that is also secreted by sympathetic neurons to activate BAT and WAT browning Several follow up studies have suggested that eosinophils, type 2 cytokines, and alternatively activated macrophages play critical roles in supporting WAT browning with concomitant increased energy expenditure and weight loss 71 — However, the notion that immune cells can influence WAT browning has recently been challenged, using different murine and in vitro approaches As such, there is some discordance regarding the role of macrophages in WAT browning, necessitating further studies.

Originally classified as a simple energy storage organ, adipose tissue is now known to function as a major endocrine system that secretes adipokines, growth factors, cytokines, and chemokines Adipokines are important mediators of various metabolic processes such as fatty acid oxidation, de-novo lipogenesis, gluconeogenesis, glucose uptake, insulin signaling, and energy expenditure in metabolically active tissues such as the liver, skeletal muscle, and brain The various adipokines secreted from adipose tissue and their functions will be described in more detail below.

The discussion will be limited to adipokines that are known to be produced to a large extent by adipocytes, in addition to other cell types within adipose tissue such as immune cells. Discovered in , leptin is a peptide hormone that is expressed exclusively by adipocytes and is essential for body weight regulation.

Leptin, adiponectin, and omentin the latter two will be described below are the only generally accepted adipokines with true endocrine function, meaning they are released from adipose tissue and exert effects on distant target organs. Leptin is encoded by the obesity gene ob.

Rodents and humans that lack either leptin or the leptin receptor LEPR are not only extremely obese, but are also hyperglycemic and extremely insulin resistant In lean and obese animals and humans, circulating leptin levels positively correlate with adiposity Prolonged fasting is associated with a sharp drop in plasma leptin levels, which drives food intake While leptin is expressed in all adipose depots, including BAT, its expression is highest in subcutaneous WAT As one of the first adipokines discovered in the mids 87 — 90 , adiponectin is a well-described insulin-sensitizing hormone that impacts a wide range of tissues.

Adiponectin is a distinctly unique adipokine, as its expression and circulating levels are inversely proportional to adiposity levels, in stark contrast to leptin. Adiponectin expression levels vary between sexes, with higher levels observed in females than males 91 — 93 , and between adipose tissue depots, with higher expression in subcutaneous than visceral WAT 94 , The insulin sensitivity-promoting properties of adiponectin are well-known, and are exemplified by the development of insulin resistance in adiponectin-deficient mice 96 , and the preservation of insulin sensitivity in adiponectin-overexpressing mice Adiponectin signals through two related receptors, ADIPOR1 and ADIPOR2, followed by docking of the adaptor protein APPL1 The resulting signaling pathway, mediated through peroxisome proliferator-activated receptor alpha PPARα , leads to metabolic improvements involving decreased hepatic gluconeogenesis, increased liver and skeletal muscle fatty acid oxidation, increased glucose uptake in skeletal muscle and WAT, and decreased WAT inflammation Thus, adiponectin receptors are highly expressed in skeletal muscle, liver, and adipose tissue.

In addition, adiponectin receptors are expressed in the pancreas, where adiponectin functions to mitigate β-cell loss by neutralizing inflammatory and lipotoxic ceramides and diacylglycerols In addition to β-cells, adiponectin has also been shown to exhibit strong anti-inflammatory effects on other cell types such as macrophages and fibrogenic cells 99 , , Taken together, adiponectin plays a protective role in mitigating features of the metabolic syndrome.

Resistin is a polypeptide that is secreted by obese adipose tissue. It was originally described as an adipocyte-specific hormone, but it is now thought to originate from macrophages residing in inflamed adipose tissue in mice and from circulating monocytes and tissue macrophages in humans , Evidence for this comes from an initial study in which it was observed that plasma resistin levels are elevated in a diet-induced obese mouse model, that blocking resistin action using a neutralizing antibody improves insulin sensitivity, and that recombinant resistin administration to healthy mice promotes insulin resistance These initial studies led to the suggestion that resistin plays an important role in modulating insulin resistance in the context of obesity, and it has been shown to correlate with insulin resistance in mice and humans Plasma resistin levels have been shown to be increased in obese animal models and humans — and to decrease with weight loss in humans Conversely, some studies have shown that adipose tissue-derived resistin is suppressed in obesity — , inciting the controversy over what role resistin plays in obesity that persists today.

Evidence suggests that visceral fat is the largest contributor to circulating resistin levels , supporting the case for an association between resistin and insulin resistance. Moreover, resistin is believed to be an active participant in propagating inflammatory responses.

Resistin can upregulate inflammatory cytokines such as TNFα and IL-6 in monocytes and macrophages in a nuclear factor kappa-B NFκB -dependent manner , and is positively associated with circulating inflammatory markers such as C-reactive protein CRP and TNFα Thus, while resistin is an established adipokine and has been shown in some cases to be associated with adverse health conditions such as obesity and insulin resistance, a clear role for resistin is still under active investigation.

Initially described as an adipokine secreted from omental WAT , it is now generally accepted that omentin is also expressed in other WAT depots such as epicardial fat, and that it derives specifically from the stromal vascular fraction of WAT , Omentin is a true endocrine hormone that circulates in the blood , Omentin levels are reduced in subjects with obesity and T2DM , , leading investigators to speculate that omentin may be involved in glucose homeostasis.

Indeed, studies using in vitro models showed that omentin enhances insulin-stimulated glucose uptake in human adipocytes by activating Akt signaling pathways , and studies in humans show a significant negative correlation between serum omentin levels as well as adipose omentin mRNA levels with insulin resistance , , Omentin levels have been shown to gradually increase in response to weight loss , Additional studies suggest that omentin has anti-inflammatory properties.

Omentin blunts cytokine expression in endothelial cells , vascular smooth muscle cells , , macrophages , cardiomyocytes , and adipose tissue itself , and is negatively associated with systemic inflammatory markers such as TNF and IL-6 Thus, omentin is considered to be a biomarker for metabolic health that may function to blunt obesity-related cytokine effects FGF21 is an endocrine hormone that is involved in the regulation of lipid, glucose, and energy homeostasis FGF21 has received a lot of attention for its insulin-sensitizing and weight loss-inducing effects when administered pharmacologically The liver is the primary source of circulating FGF21, induced by metabolically stressful conditions such as fasting, a ketogenic diet, protein restriction, and bariatric surgery , while the brain and adipose tissue are primary FGF21 targets , Other tissues are known to also secrete FGF21, including the pancreas and skeletal muscle , However, under certain metabolic conditions such as obesity, WAT and BAT may also produce FGF21 This is supported by several studies showing that BMI and adiposity positively correlate with circulating FGF21 levels in mice and humans — It is clear that FGF21 levels become elevated as obesity develops in mice and humans, and are positively correlated with BMI, adiposity, and FGF21 expression levels in adipose tissue — While many studies have shown that adipose tissue expresses FGF21 in rodents , — , there is still some debate about whether FGF21 is readily expressed in human adipose tissue.

There are a handful of studies that suggest that adipose tissue FGF21 mRNA expression is below detection levels or not expressed by adipose tissue However, numerous additional studies have found detectable FGF21 mRNA expression in visceral WAT , , subcutaneous WAT , , , epicardial WAT , cervical adipose tissue , , and PVAT , , with the latter two depots containing both WAT and BAT.

FGF21 protein has also been detected in adipose tissue by Western blot and immunohistochemistry Some studies suggest that adipose-derived FGF21 is a marker of metabolic stress, as it has been shown to correlate with features of the metabolic syndrome , , Regardless, a clearly-defined function of adipose-derived FGF21 has not yet been established, nor whether adipose-derived FGF21 promotes primarily local effects or contributes to the circulating FGF21 pool under particular metabolic conditions.

Elegant studies using tissue-specific Fgf21 KO mice show that adipocyte-derived Fgf21 is not involved in obesity-associated insulin resistance, and that adipose-derived Fgf21 doesn't circulate, instead acting in a paracrine fashion However, the mice used in that study were fasted for 24 h, introducing a metabolic stress that would likely only induce liver-derived Fgf21 that may have masked any contribution from adipose-derived Fgf In later studies, a thermogenic role for adipose-derived Fgf21 has been described, in which the browning of WAT was shown to require adipocyte-Fgf21 , Thus, it is possible that hepatic- and adipose-derived FGF21 are induced by different stimuli, and that more studies are required to conclusively define a role for adipose-derived FGF Obesity results when energy intake chronically exceeds energy expenditure.

Many factors are involved, including genetic, epigenetic, hormonal, and lifestyle factors that are beyond the scope of this review. Adipocyte number is believed to be tightly regulated and determined during childhood However, during the development of obesity, adipose tissue can expand by either hypertrophy an increase in adipocyte size or hyperplasia an increase in adipocyte number due to the recruitment of new adipocytes.

Obesity is characterized by dysfunctional adipose tissue, in which adipocytes initially become hypertrophic during periods of caloric excess and secrete adipokines that result in the recruitment of additional pre-adipocytes, which differentiate into mature adipocytes as compensatory protection against some of the adverse metabolic consequences of obesity This concept is supported by observations in AdipoChaser mice, a model for tracking adipogenesis AdipoChaser mice fed a high fat diet display evidence of hypertrophy of visceral WAT within 1 month, while hyperplasia occurs after 2 months.

Importantly, subcutaneous WAT does not undergo hyperplasia, and hypertrophy lags behind the visceral compartment, with evidence of subcutaneous WAT hypertrophy after 2 months of high fat feeding However, when the capacity for adipocyte recruitment and hypertrophy is overwhelmed, fat accumulates in ectopic sites such as visceral depots, the liver, skeletal muscle, and pancreatic beta cells.

These changes are accompanied by inflammation, insulin resistance and other features of the metabolic syndrome, and have been termed metabolically unhealthy obesity MUHO , In contrast to MUHO, some people accumulate fat mainly in subcutaneous depots, a condition that has been termed metabolically healthy obesity MHO.

MHO is not accompanied to any great extent by insulin resistance, adipose tissue and systemic inflammation, and other features of the metabolic syndrome such as dyslipidemia and hypertension — Thus, the distribution of fat accumulation is a major determinant of metabolic complications associated with obesity, which can increase the risk of CVD.

Various features that contribute to dysfunctional WAT in obesity will be discussed in the sections that follow. A sub-group of obese individuals remain insulin-sensitive, and exhibit normal metabolic and hormonal profiles despite having a BMI that would characterize them as obese , Therefore, MHO individuals have a lower risk for developing T2DM and cardiovascular disease MHO is sometimes defined as having 2 or less features of the metabolic syndrome or based on homeostatic model assessment of insulin resistance HOMA-IR measures, but consensus on a precise definition does not exist Thus, some individuals classified as having MHO rather fall somewhere between metabolically healthy and unhealthy.

Moreover, individuals with so-called MHO can progress to develop features of the metabolic syndrome with time — Because CVD outcomes in general relate to the number of metabolic abnormalities present in individuals with MUHO — , there is less CVD in individuals with MHO than those with the metabolic syndrome.

In addition, while MHO individuals are so defined due to a healthier cardiometabolic profile than those with MUHO, the true clinical benefits of MHO remain in question, as the cardiometabolic profile and insulin sensitivity of MHO individuals typically does not improve significantly with weight loss , — Nevertheless, evidence from animal models and cultured adipocytes do suggest that the preservation of the capacity for subcutaneous WAT expansion mitigates extensive visceral and hepatic fat accumulation, potentially driving the MHO phenotype 76 , 97 , Other obese individuals tend to accumulate fat mainly intra-abdominally in visceral depots, which is also known as central obesity.

Visceral adiposity is associated with insulin resistance, a predisposition to diabetes, local and systemic inflammation, dyslipidemia [characterized by hypertriglyceridemia, a preponderance of small, dense low-density lipoprotein LDL particles and reduced high-density lipoprotein HDL -cholesterol levels], insulin resistance, dysglycemia [a broad term that refers to an abnormality in blood sugar stability], adipose tissue and systemic inflammation, hypertension, a thrombogenic profile and non-alcoholic fatty liver disease NAFLD This constellation of CVD risk factors associated with visceral obesity is widely known as the metabolic syndrome and is a hallmark of MUHO, illustrated in Figure 1.

Visceral obesity and the metabolic syndrome are associated with an increased risk of developing CVD, which is exacerbated when overt diabetes develops as a result of insulin secretion failing to adequately compensate for insulin resistance. Interestingly, even normal weight individuals who accumulate fat intra-abdominally have these metabolic abnormalities , , including an increased risk of CVD.

Asians and Asian-Americans are particularly prone to accumulate intra-abdominal fat and have features of the metabolic syndrome despite having normal weights and BMI values by Western standards , raising the question of whether different normal values should apply to individuals of Asian ancestry.

These indexes are notable for their inclusion of upper subcutaneous WAT, which some consider to contribute as much, if not more, to metabolic syndrome than visceral WAT alone CT scanning at the level of the umbilicus has been found to be useful but is expensive and not practical other than for research purposes at present.

Lower body subcutaneous WAT does not correlate with risk factors for the metabolic syndrome, potentially due to a slower FFA turnover, higher levels of adipocyte hyperplasia, and lower levels of inflammation — Figure 1.

Metabolically healthy obesity MHO vs. metabolically unhealthy obesity MUHO. In comparison with lean metabolically healthy subjects, those with MHO have increased adiposity and BMI, but with reduced systemic inflammation and retained insulin sensitivity, thus defining them as not having metabolic syndrome MetS.

MHO subjects have elevated subcutaneous white adipose tissue WAT levels, without excessive accumulation of visceral fat. Their adipokine profile is similar to lean subjects, but with increased leptin, resistin, and FGF21, and decreased adiponectin, which limits their risk of developing type 2 diabetes mellitus T2DM and cardiovascular disease CVD in the short term.

By contrast, those with MUHO exhibit elevated insulin resistance and systemic inflammation in addition to increased adiposity and BMI over lean controls, contributing to MetS.

MUHO individuals have excess subcutaneous and intra-abdominal adipose tissue, with increased hepatic fat and fat distributed amongst other visceral organs. This leads to a dysfunctional adipokine profile, characterized by reduced adiponectin and omentin, with further elevated leptin, resistin, FGF21, and cytokines when compared to lean controls.

Thus, MUHO subjects are at risk for developing T2DM and CVD. Notable differences in the adipokine profile between MHO and MUHO subjects have been reported, which could contribute to their respective risks for T2DM and CVD.

Leptin has been shown to be higher in MUHO than MHO obese Chinese children in one study , but was not found to differ between adult groups in several other studies — By contrast, adiponectin has consistently been shown to be higher in subjects with MHO than in those with MUHO, despite both populations having lower adiponectin than metabolically healthy lean controls , — Resistin and FGF21 levels tend to be highest in the MUHO population , Data on whether omentin levels differ between MHO and MUHO has been inconsistent, with one study suggesting that MUHO subjects have higher omentin levels than MHO subjects , and other suggesting the opposite, that omentin levels are negatively correlated with the metabolic syndrome , Cytokines such as TNFα and IL-6 as well as the chemokines SAA and MCP-1 have been shown to be elevated in MUHO These adipokine differences between subjects with MHO and MUHO are depicted in Figure 1.

Adipose tissue expansion in obesity is accompanied by inflammatory changes within adipose tissue, contributing to chronic low-grade systemic inflammation that is characterized as mildly elevated levels of circulating cytokines, chemokines, and acute phase reactants. Expansion of adipose tissue depots during weight gain is accompanied by an infiltration of new inflammatory cells, the major one initially being macrophages.

These pro-inflammatory cells are recruited in response to chemokines such as monocyte chemotactic protein-1 MCP-1 produced by hypertrophic adipocytes , Studies in mice have demonstrated that most macrophages in obese adipose tissue are derived from circulating monocytes , although a small percentage appear to derive from proliferation of resident tissue macrophages These anti-inflammatory macrophages are believed to be responsible for maintaining tissue homeostasis It remains unclear whether the derivation of adipose tissue macrophages is the same in human obesity.

Macrophage accumulation occurs to a greater extent in visceral than in subcutaneous adipose depots in both rodents and humans — Macrophages are seen in crown-like clusters, where they are thought to represent an immune response to dead and dying adipocytes However, use of genetic markers show that these cells have significant differences from classical M1 macrophages and alternate nomenclatures have been suggested for these pro-inflammatory cells.

Morris and Lumeng have divided adipose tissue macrophages into several populations based on cell surface markers and expression profiling Using a proteomics approach, Kratz et al.

showed that markers of classical activation were absent on ATMs from obese humans. Such markers of metabolic activation were expressed by pro-inflammatory macrophages in adipose tissue from obese humans and mice and correlated with the extent of adiposity In addition to macrophages, T-cells also are present in normal adipose tissue and demonstrate phenotypic change during weight gain.

Th2 cytokines e. With weight gain in mice there is a shift away from a predominance of TH2 T cells present in lean adipose tissue and toward more TH1 and cytotoxic T cells as well as a reduction in regulatory T cells Tregs Interferon γ IFNγ —expressing Th1 polarized T cells appear to promote adipose tissue inflammation and increased IFN-γ activity has been reported in adipose tissue in both mice and humans , A subset of T cells called natural killer T NKT cells respond to lipid or glycolipid antigens — The number of invariant NKT iNKT numbers has been observed to be reduced in adipose tissue and livers from obese mice and humans — B-cells and mast cells also are increased in adipose tissue in the obese state , , Use of specific cell surface markers has also demonstrated the presence of dendritic cells in adipose tissue, and studies indicate that dendritic cells are independent contributors to adipose tissue inflammation during obesity , There is good evidence to support the notion that the systemic inflammation that is associated with obesity and contributes to insulin resistance begins with adipose tissue inflammation.

The regulation of hepatic C-reactive protein CRP and serum amyloid A SAA is likely in response to IL-6 secretion from visceral adipose tissue that directly targets the liver via the portal circulation — CRP is a prominent biomarker for insulin resistance and CVD — , and SAA antagonizes insulin action in adipocytes, thus contributing to systemic insulin resistance SAA also has been associated with CVD in some rodent and human models , — On the other hand, they showed that males at any age tend to accumulate fat at the visceral depot, increasing with age and BMI increase.

In the male, a close linear correlation between age and visceral fat volume was shown, suggesting that visceral fat increased continuously with age Although this correlation was also present in women, the slope was very gentle in the premenopausal condition.

It became steeper in postmenopausal subjects, almost the same as in males Further, Enzi et al. From the published data 68 , 90 , it can be concluded that both subcutaneous and visceral abdominal fat increase with increasing weight in both sexes but while abdominal subcutaneous adipose tissue decreases after the age of 50 yr in obese men, it increases in women up to the age of 60—70 yr, at which point it starts to decline Fowler et al.

Finally, as previously indicated, visceral fat is more sensitive to weight reduction than subcutaneous adipose tissue because omental and mesenteric adipocytes, the major components of visceral abdominal fat, have been shown to be more metabolically active and sensitive to lipolysis Lemieux et al.

In addition, the adjustment for differences in visceral fat between men and women eliminated most of the sex differences in cardiovascular risk factors. There is evidence supporting the notion that abdominal visceral fat accumulation is an important correlate of the features of the insulin-resistant syndrome 23 , 24 , 29 but this should not be interpreted as supporting the notion of a cause and effect relationship between these variables This subject will be discussed later on.

The correlations of abdominal visceral fat mass evaluated by CT or MRI scans with total body fat range from 0. They tend to be lower in the lean and normal weight subjects than in the obese As indicated by Bouchard et al. When they examined the relationship of total body fat mass to visceral adipose tissue accumulation in men and in premenopausal women, Lemieux et al.

Furthermore, the relationship of visceral adipose tissue to metabolic complications was found to be independent of concomitant variation in total body fat, and it was concluded that the assessment of cardiovascular risk in obese patients solely from the measurement of body weight or of total body fatness may be completely misleading 19 , 22 , 36 , Indeed, it appears that only the subgroup of obese individuals characterized by a high accumulation of visceral adipose fat show the complications predictive of type 2 diabetes and cardiovascular disease On the other hand, after adjustment for total body fat, Abate et al.

Intraabdominal visceral fat is associated with an increase in energy intake but this is not an absolute requirement. Positive energy balance is a strong determinant of truncal-abdominal fat as shown by Bouchard and colleagues 96 in overfeeding experiments in identical twins.

The correlations between gains in body weight or total fat mass with those in subcutaneous fat on the trunk reached about 0. In contrast, these correlations attained only 0. Thus, positive energy balance does not appear to be a strong determinant of abdominal visceral fat as is the case with other body fat phenotypes 7.

In effect, as discussed in the CT section of imaging techniques for evaluation of intraabdominal visceral fat, some investigators 70 , 71 have shown that either when the subjects lose or increase their weight, particularly females, visceral fat is lost or gained, respectively, less than subcutaneous fat at the abdominal level.

However, at variance from these data, Zamboni et al. Similarly, as already mentioned, Smith and Zachwieja 32 noted that all forms of weight loss affect visceral fat more than subcutaneous fat percentage wise , and there was a gender difference, with men appearing to lose more visceral fat than women for any given weight loss.

LPL activity, being related to the liberation of the lipolytic products [from chylomicra and very-low-density lipoproteins VLDL ] to the adipocytes for deposit as triglycerides, is a key regulator of fat accumulation in various adipose areas, since human adipose tissue derives most of its lipid for storage from circulating triglycerides.

However, adipocytes can synthesize lipid de novo if the need arises, as in patients with LPL deficiency According to Sniderman et al. The increase of visceral fat masses with increasing total body fat was explained by an increase of fat cell size only up to a certain adipocyte weight.

However, with further enlargement of intraabdominal fat masses with severe obesity, the number of adipocytes seems to be elevated , In women, but not in men, omental adipose tissue has smaller adipocytes and lower LPL activity than subcutaneous fat depots since variations in LPL activity parallel differences in fat cell size 7.

When adipocytes enlarge in relation to a gain in body weight, the activity of LPL increases in parallel, possibly as a consequence of obesity-related hyperinsulinism. The higher basal activity of adipose tissue LPL in obesity is accompanied by a lower increment after acute hyperinsulinemia Lipid accumulation is favored in the femoral region of premenopausal women in comparison with men In the latter, LPL activity as well as the LPL mRNA levels were greater in the abdominal than in gluteal fat cells, while the opposite was observed in women, suggesting that regional variation of gene expression and posttranslational modification of LPL could potentially account for the differences between genders in fat distribution With progressive obesity, adipose tissue LPL is increased in the depots of fat in parallel with serum insulin.

However, when obese subjects lost weight and became less hyperinsulinemic, adipose LPL increased further and the patients who were most obese showed the largest increase in LPL, suggesting that very obese patients are most likely to have abnormal LPL regulation, independent of the influence of insulin.

In response to feeding, the increase in LPL is, as indicated, due to posttranslational changes in the LPL enzyme. However, the increased LPL after weight loss involved an increase in LPL mRNA levels, followed by parallel increases in LPL protein and activity Because the response to weight loss occurred via a different cellular mechanism, it is probably controlled by factors different from the day-to-day regulatory forces.

In addition, because the very obese patients demonstrated a larger increase in LPL with weight loss than the less obese patients, these data suggest a genetic regulation of LPL that is most operative in the very obese The role of sex steroids, glucocorticoids, and catecholamines in the regulation of adipose tissue LPL activity in various fat depots will be discussed in the section on hormonal regulation of abdominal visceral fat.

Lipid mobilization and the release of FFA and glycerol are modulated by the sympathetic nervous system. Catecholamines are the most potent regulators of lipolysis in human adipocytes through stimulatory β l - and β 2 -adrenoreceptors or inhibitoryα 2-adrenoreceptors A gene that codes for a third stimulatory β -adrenoreceptor, β 3 -adrenoreceptor, is functionally active principally in omental adipocytes but also present in mammary fat and subcutaneous fat in vivo In both genders and independently of the degree of obesity, femoral and gluteal fat cells exhibit a lower lipolytic response to catecholamines than subcutaneous abdominal adipocytes, the latter showing both increased β l - and β 2 -adrenoreceptor density and sensitivity and reduced α2-adrenoreceptor affinity and number Refs.

The increased sensitivity to catecholamine-induced lipolysis in omental fat in nonobese individuals is paralleled by an increase in the amount of β l - and β 2 -receptors, with normal receptor affinity and normal lipolytic action of agonists acting at postadrenoreceptor steps in the lipolytic cascade , ; this is associated with enhanced β 3 -adrenoreceptor sensitivity, which usually reflect changes in receptor number in comparison with subcutaneous adipocytes , Comparison of lipolysis, antilipolysis, and lipogenesis in omental and subcutaneous fat in nonobese and obese individuals.

Adipocytes from obese subjects generally show increased lipolytic responses to catecholamines, irrespective of the region from which they are obtained, and enhanced lipolysis in abdominal compared with gluteo-femoral fat 21 , The antilipolytic effect is also reduced in vitro in obesity, both in omental and subcutaneous adipocytes The typical features of visceral fat, e.

An increased β 3 -adrenoreceptor sensitivity to catecholamine stimulation may lead to an increased delivery of FFA into the portal venous system, with several possible effects on liver metabolism. These include glucose production, VLDL secretion, and interference with hepatic clearance of insulin , resulting in dyslipoproteinemia, glucose intolerance, and hyperisulinemia.

Lönnqvist et al. They observed that males had a higher fat cell volume with no sex differences in the lipolytic sensitivity to β l - and β 2 -adrenoreceptor-specific agonists or in the antilipolytic effect of insulin.

However, the lipolytic β 3 -adrenoreceptor sensitivity was 12 times higher in men, and the antilipolytic α2-adrenoreceptor sensitivity was 17 times lower in men.

It was concluded that in obesity, the catecholamine-induced rate of FFA mobilization from visceral fat to the portal venous system is higher in men than women. This phenomenon is partly due to a larger fat cell volume, a decrease in the function ofα 2-adrenoceptors, and an increase in the function of β 3 -adrenoreceptors.

These factors may contribute to gender-specific differences observed in the metabolic disturbances accompanied by obesity, i. Glucocorticoid receptors. Glucocorticoid receptors, one of the most important receptors for human adipose tissue function, are involved in metabolic regulation and distribution of body fat under normal as well as pathophysiological conditions.

Glucocorticoid receptors in adipose tissue show a regional variation in density with elevated concentrations in visceral adipose tissue In spite of the lower receptor density, the elevated cortisol secretion results in clearly increased net effects of cortisol.

Androgen and estrogen receptors. Adipocytes have specific receptors for androgens, with a higher density in visceral fat cells than in adipocytes isolated from subcutaneous fat.

Unlike most hormones, testosterone induces an increase in the number of androgen receptors after exposure to fat cells , thereby affecting lipid mobilization.

This is more apparent in visceral fat omental, mesenteric, and retroperitoneal because of higher density of adipocytes and androgen receptors, in addition to other factors However, at variance with the effects of testosterone, dihydrotestosterone treatment does not influence lipid mobilization In females, there is an association between visceral fat accumulation and hyperandrogenicity, despite the documented effects of testosterone on lipid mobilization and the expected decrease in visceral fat depots.

The observation that visceral fat accumulation occurs only in female-to-male transsexuals after oophorectomy suggests that the remaining estrogen production before oophorectomy was protective The androgen receptor in female adipose tissue seems to have the same characteristics as that found in male adipose tissue.

However, estrogen treatment down-regulates the density of this receptor, which might be a mechanism whereby estrogen protects adipose tissue from androgen effects.

Estrogen by itself seems to protect postmenopausal women receiving replacement therapy from visceral fat accumulation Estrogen receptors are expressed in human adipose tissue and show a regional variation of density, but whether the quantity of these receptors is of physiological importance has not been clearly established With regard to progesterone, adipose cells seem to lack binding sites and mRNA for progesterone receptors, indicating that progesterone acts through glucocorticoid receptors GH receptors.

While it is well established that GH has specific and receptor-mediated effects in adipose tissue of experimental animals, the importance of GH receptors in human adipose tissue is not fully elucidated at present although the available data indicate a functional role.

However, GH is clearly involved in the regulation of visceral fat mass in humans. Acromegaly, a state of GH excess, is associated with decreased visceral fat while in GH deficiency there is an increase in visceral fat and in adults with GH deficiency, recombinant human GH replacement therapy results in adipose tissue redistribution from visceral to subcutaneous locations; however, the regulation of adipose tissue metabolism requires synergism with steroid hormones A direct demonstration of a regulation of the GH receptor in human fat cells has not yet been performed Thyroid hormone receptors.

Thyroid hormones have multiple catabolic effects on fat cells as a result of interactions with the adrenergic receptor signal transduction system, and most of these interactions are also present in human fat cells There are data regarding the characterization of the nuclear T 3 receptor in human fat cells Although receptor regulation has not yet been demonstrated, there is little doubt that the thyroid hormone receptors are important for the function of human adipose tissue Further, no data are available on the correlation between visceral fat mass and thyroid hormone levels.

Adenosine receptors. Adenosine behaves as a potent antilipolytic and vasodilator agent and can be considered as an autocrine regulator of both lipolysis and insulin sensitivity in human adipose tissue. Site differences in ambient adenosine concentration, perhaps controlled by blood flow, may also modulate adipose tissue metabolism 7.

Adenosine content is higher in omental than in abdominal subcutaneous adipose tissue, but the receptor-dependent inhibition of lipolysis is, as indicated before , less pronounced in the former than in the latter depot However, despite strong antilipolytic effect of adenosine analogs, human adipocytes contain few adenosine type A l receptors, regardless of the fat depot considered According to Arner , the α2-, β l -,β 2 -, and β 3 -adrenoreceptors and receptors for insulin, adenosine, and glucocorticoids, as well as for PGE 2 , a potent antilipolytic agent with high affinity receptors identified in adipocytes , have a major functional role, as shown by relevant biological receptor-mediated effects, the presence of a receptor molecule, and receptor regulation.

The receptors for GH, thyroid hormones, estrogen, and testosterone, as well as for acetylcholine and TSH, probably have an important functional role but complete evidence, indicated in the previous group of receptors, is not present so far; however, there is little doubt of a regulatory role.

Genetic epidemiology: heritability and segregation analysis. Studies performed in individuals from families of French descent living in Quebec City [Quebec Family Study QFS ] allowed the estimation of the fraction of the phenotypic variance that could be attributed to the genetic and environmental factors among the obesity phenotypes or in the distribution of the adipose tissue, taking into account the BMI and amount of subcutaneous fat by the sum of the measurement of skinfolds in six different sites , lean body mass, fat mass, percentage of fat derived from underwater weighing, and visceral fat by CT , The residual variance corresponded to environmental factors, but some factors cultural, nongenetic could be transmitted from parents to descendents and sometimes were confounded by genetic effects Segregation analysis studies have recently concluded that visceral fat is similarly influenced by a gene with a major effect in the QFS and HERITAGE families , However, after adjustment of the visceral adipose tissue for the fat mass, the effect of the gene with the major effect was not more compatible with a mendelian transmission.

These results suggested the presence of a pleiotropism: the gene with the major effect, identified by the fat mass , could similarly influence the amount of visceral fat Similar results were obtained with the same type of analysis in the HERITAGE cohort To test the hypothesis of a genetic pleiotropism, Rice et al.

The results of this study Fig. These results have confirmed the presence of a genetic pleiomorphism and suggested the presence of genes affecting simultaneously the amounts of fat mass and visceral abdominal fat. Schematic representation of the genetic effects on total fat mass and visceral fat adjusted for the fat mass and on the co-variation between the two phenotypes Quebec Family Study, G 1 and G 2 represent the genetic effects specific for the total fat mass and visceral fat, respectively.

E 1 and E 2 represent the specific effects of the environment on total fat mass and visceral fat, respectively. G 3 and E 3 indicate the genetic and environment effects common to both phenotypes. Pérusse et al. The interactions of the effects of genotype and environment evaluated in monozygotic twins, when the energy balance is manipulated, indicated that even though there were large interindividual differences in the response to excess or negative energy balance, there was a significant within-pair resemblance in response 96 , In effect, in response to overfeeding, there was at least 3 times more variance in response between pairs than within pairs for the gains in body weight, fat mass, and fat-free mass In relation to the response to the negative energetic balance, at least 7 times more variation was observed in response between pairs than within members of the same pair of twins, with respect to the same variables This intrapair similarity in the response to either excess or deficient energy balance is also observed in relation to the abdominal visceral fat Thus, the interaction between genotype and environment is important to consider in the study of the genetics of obesity since the propensity to fat accumulation is influenced by the genetic characteristics of the subject.

Molecular genetics: association and linkage studies. Several candidate genes as well as random genetic markers were found to be associated with obesity as well as body fat and fat distribution in humans. The current human obesity gene map, based on results from animal and human studies, indicates that all chromosomes, with the exception of the Y chromosome, include genes or loci potentially involved in the etiology of obesity Initial findings from the QFS showed that significant but marginal associations with body fat were found with LPL and the α2-subunit of the sodium-potassium ATPase genes The Trp64Arg mutation of the β 3 -adrenergic receptor gene β 3 AR , prevalent in some ethnic groups, is associated with visceral obesity and insulin resistance in Finns as well as increased capacity to gain weight This mutation was also shown to be associated with abdominal visceral obesity in Japanese subjects, with lower triglycerides in the Trp64Arg homozygotes but not heterozygotes It has been suggested that those with the mutation may describe a subset of subjects characterized by decreased lipolysis in visceral adipose tissue.

On the other hand, Vohl et al. Previously, it was reported by the same group that apo-B gene Eco R-1 polymorphism appeared to modulate the magnitude of the dyslipidemia generally found in the insulin-resistant state linked with visceral obesity These studies are a demonstration of a significant interaction between visceral obesity and a polymorphism for a gene playing an important role in lipoprotein metabolism.

When the genes related to the hormonal regulation of body fat distribution studied in the QFS families sex hormone-binding globulin, 3β-hydroxysteroid dehydrogenase, and glucocorticoid receptor genes were considered along with the knowledge that body fat distribution is influenced by nonpathological variations in the responsiveness to cortisol, it was shown that the less frequent 4.

However, the association with abdominal visceral fat area was seen only in subjects of the lower tertile of the percent body fat level. The consistent association between the glucocorticoid receptor polymorphism detected with Bcl I and abdominal visceral fat area suggested that this gene or a locus in linkage disequilibrium with the Bcl I restriction site may contribute to the accumulation of abdominal visceral adipose tissue With respect to the linkage studies, only a few studies of body fat or fat distribution with random genetic markers or candidate genes have been reported using the sibling-pair linkage method.

One of the few reported studies relative to the visceral fat mass was the evaluation of a sib-pair linkage analysis from the QFS between five microsatellite markers encompassing about 20 cM in the Mob-1 region of the human chromosome 16pp These results suggested to the authors that this region of the human genome contains a locus affecting the amount of visceral fat and lipid metabolism as also shown by the association studies indicated above.

The other population and intrafamily association study used a polymorphic marker LIPE in the hormone-sensitive lipase gene, located on chromosome 19q In conclusion, despite the fact that the genetic architecture of obesity has just begun, the results obtained so far suggest that a great number of genes, loci, or chromosomal regions distributed on different chromosomes could play a role in determining body fat and fat distribution in humans.

This reflects the complex and heterogeneous nature of obesity. The accumulation of adipose tissue in the abdominal region is at least partially influenced by genes, which becomes more evident as the number of involved genes are identified.

The concept that adipocytes are secretory cells has emerged over the past few years. Adipocytes synthesize and release a variety of peptide and nonpeptide compounds; they also express other factors, in addition to their ability to store and mobilize triglycerides, retinoids, and cholesterol.

These properties allow a cross-talk of adipose tissue with other organs as well as within the adipose tissue. The important finding that adipocytes secrete leptin as the product of the ob gene has established adipose tissue as an endocrine organ that communicates with the central nervous system.

As already mentioned, LPL is the key regulator of fat cell triglyceride deposition from circulating triglycerides. LPL is found, after transcytosis, associated with the glycosaminoglycans present in the luminal surface of the endothelial cells. The regulation of LPL secretion, stimulated by the most important hormonal regulator, insulin, is related to posttranslational changes in the LPL enzyme, at the level of the Golgi cisternae and exocytotic vesicles, insulin possibly having a positive role in this secretory process Genes encoding LPL were not differentially expressed in omental when compared with subcutaneous adipocytes However, in very obese individuals omental adipocytes express lower levels of LPL protein and mRNA than do subcutaneous fat cells The regulation of LPL in obesity has been presented in the Section on correlations of abdominal visceral fat.

With respect to the hormonal regulation of LPL, insulin and glucocorticoids are the physiological stimulators of the LPL activity, and their association plays an important role in the regulation of body fat topography. In effect, omental adipose tissue is known to be less sensitive to insulin, both in the suppression of lipolysis and in the stimulation of LPL However, when exposed to the combination of insulin plus dexamethasone in culture for 7 days, large increases in adipose LPL were observed because of increases in LPL mRNA Significant differences were observed between men and women.

The increase in LPL in response to dexamethasone suggests that the well known steroid-induced adipose redistribution especially in the abdomen may be caused by increases in LPL, which would lead to a preferential distribution of plasma triglyceride fatty acids to the abdominal depot. Therefore, these data suggest that LPL is central to the development of abdominal visceral obesity On the other hand, catecholamines, GH, and testosterone in males reduce adipose tissue LPL Acylation-stimulating protein ASP.

ASP is considered the most potent stimulant of triglyceride synthesis in human adipocytes yet described. Its generation is as follows Human adipocytes secrete three proteins of the alternate complement pathway: C3 the third component of the complement , factor B, and factor D adipsin , which interact extracellularly to produce a amino-terminal fragment of C3 known as C3a.

Excess carboxypeptidases in plasma rapidly cleave the terminal arginine from C3a to produce the amino acid peptide known as C3a desarg or ASP, which then acts back upon the adipocyte, causing triglyceride synthesis to increase. As fatty acids are being liberated from triglyceride-rich lipoproteins and chylomicrons as the result of the action of LPL, ASP is also being generated and triglyceride synthesis increased concurrent with the need to do so.

In human adipose tissue, in the postprandial period, ASP secretion and circulating triglycerides clearance are coordinated in accordance with the suggestion that ASP in sequence to LPL would have a paracrine autoregulatory role. The adipsin-ASP pathway, therefore, links events within the capillary space to the necessary metabolic response in the subendothelial space, thus avoiding the excess buildup of fatty acids in the capillary lumen.

The generation of ASP is triggered by chylomicrons. While insulin decreases gene expression of C3, B, and adipsin, it enhances the secretion of ASP as expected from the concurrent action of LPL and ASP.

However, more intensely and independent of insulin, ASP is capable of stimulating triglyceride synthesis in adipocytes and fibroblasts. Thus, from the reduced sensitivity to insulin in the suppression of lipolysis and stimulation of LPL by the omental adipose tissue, omental obesity may represent an example of impaired activity of the ASP pathway even if dysfunction of the pathway is a secondary feature.

As a consequence, omental adipose tissue, as compared with subcutaneous fat tissue, would have a limited capacity to prevent fatty acids from reaching the liver, which may contribute to the abnormalities in metabolism observed in visceral obesity Cholesteryl-ester transfer protein CETP.

Human adipose tissue is rich in CETP mRNA, probably one of the major sources of circulating CETP in humans. CETP promotes the exchange of cholesterol esters of triglycerides between plasma lipoproteins.

In this way, the adipose tissue is a cholesterol storage organ in humans and animals; peripheral cholesterol is taken up by HDL species, which act as cholesterol efflux acceptors, and is returned to the liver for excretion , The few studies of circulating CETP in obesity have shown that activity and protein mass of CETP are both significantly increased in obesity, being negatively correlated with HDL cholesterol and the cholesteryl ester-triglyceride ratio of HDL2 and HDL3, thus exhibiting an atherogenic lipoprotein profile.

Furthermore, there was a positive correlation with fasting plasma insulin and blood glucose, suggesting a possible link to insulin resistance — From an observation of Angel and Shen , it could be suggested that the CETP activity of omental adipose tissue is greatly increased in comparison with subcutaneous fat.

Retinol-binding protein RBP. Adipose tissue is importantly involved in retinoid storage and metabolism. RBP is synthesized and secreted by adipocytes , the rate of RBP gene transcription being induced by retinoic acid The mRNA encoding RBP is expressed at a relatively high level in adipocytes with no difference between subcutaneous and omental fat cells There are no data regarding retinol mobilization from adipose stores in humans; however, in vitro studies with murine adipocytes showed that the cAMP-stimulated retinol efflux from fat cells was not the result of increased RBP secretion but instead due to the hydrolysis of retinyl esters by the cAMP-dependent hormone-sensitive lipase PAI-1 is a serine protease inhibitor and evidence suggests that it is a major regulator of the fibrinolytic system, the natural defense against thrombosis.

It binds and rapidly inhibits both single- and two-chain tissue plasminogen activator tPA and urokinase plasminogen activator uTPA , which modulate endogenous fibrinolysis. The major sources of PAI-1 synthesis are hepatocytes and endothelial cells, but platelets, smooth muscle cells, and adipocytes are also contributors The increased gene expression and secretion of PAI-1 by adipose tissue contribute to its elevated plasma levels in obesity, presenting a strong correlation with parameters that define the insulin resistance syndrome, in particular with fasting plasma insulin and triglycerides, BMI, and visceral fat accumulation: omental adipose tissue explants produced significantly more PAI-1 antigen than did subcutaneous tissue from the same individual, and transforming growth factor-βl increased PAI-1 antigen production In a premenopausal population of healthy women with a wide range of BMI, there was a positive correlation of PAI-1 activity with CT-measured visceral fat area, independent of insulin and triglyceride levels.

Weight loss confirmed this link. PAI-1 diminution was correlated only with visceral adipose tissue area loss and not with total fat, insulin, or triglyceride decrease Results from in vitro studies have shown that insulin — stimulates PAI-1 production by cultured endothelial cells or hepatocytes.

Attempts to extrapolate these in vitro data to in vivo proved difficult. Acute 2-h hyperinsulinemia modulation of plasma insulin in humans did not affect PAI-1 levels, and hypertriglyceridemia from several origins was not always associated with increased PAI-1 levels In the same way, exogenous short-term insulin infusion with triacylglycerol and glucose failed to demonstrate elevations of PAI-1 The augmentation of PAI-1 by insulin probably requires concomitant elevation of lipids and glucose and perhaps other metabolites in blood, as suggested by the strikingly synergistic effects when Hep G2 cells are exposed to both insulin and fatty acids in vitro Accordingly, a hyperglycemic hyperinsulinemic clamp associated with an intralipid infusion for 6 h, to induce hyperinsulinemia combined with hyperglycemia and hypertriglyceridemia, produced an increase in PAI-1 concentrations in blood for as long as 6 h after cessation of the infusion However, the extent to which elevation of any one constituent or any given combination of elevations is sufficient to induce the phenomenon has not yet been elucidated in insulin-resistant patients.

In effect, the reduction of PAI-1 after weight loss related more to the degree of weight reduction than to triglyceride or insulin changes, as above indicated, and the lack of increase of PAI-1 in type 2 diabetics without obesity , strongly suggesting that visceral fat is an important contributor to the elevated plasma PAI-1 level observed in visceral obesity independent of insulin, triglyceride, and glucose level.

Finally, prospective cohort studies of patients with previous myocardial infarction or angina pectoris have underlined the association between an increase in plasma PAI-1 levels and corresponding defective fibrinolysis and the risk of atherosclerosis and thrombosis, particularly in relation to coronary events , thus linking visceral fat accumulation to macrovascular disease Recently, it was shown that in addition to insulin, corticosteroids dexamethasone and hydroxycorticosterone affect PAI-1 synthesis by human subcutaneous adipose tissue explants in a dose-dependent manner; this model showed the regulation of PAI-1 by adipose tissue after validation by showing a high correlation between the production of PAI-1 by omental and subcutaneous fat In the same way, it was demonstrated that PAI-1 production was significantly correlated with that of tumor necrosis factor-α TNFα , emphasizing a possible local contribution of TNFα in the regulation of PAI-1 production by human adipose tissue P aromatase activity in adipose tissue is important for estrogen production, which may have a paracrine role, since, as previously indicated, estrogen receptors are expressed in human adipose tissue In effect, estrone, the second major human circulating estrogen in premenopausal women and the predominant one in postmenopausal women, is mostly derived from the metabolism of ovarian-secreted estradiol catalyzed by 17β-hydroxy steroid dehydrogenase and from aromatization of androstenedione in adipose tissue in the former and almost exclusively by aromatization of that C19 androgen secreted by the adrenals in the latter.

The peripheral aromatization of testosterone to estradiol and estrone contributes minimally to estradiol and estrone production The conversion rate of androstenedione to estrone increases as a function of aging and obesity [due to an increase in adipose tissue P aromatase transcript levels, highest in the buttocks, next highest in the thighs, and lowest in the subcutaneous abdominal tissue , ] and significantly greater in women with lower gynoid obesity than in upper body obesity In obese men, the peripheral conversions of testosterone to estradiol and androstenedione to estrone, as well as the circulating levels of those estrogens, are also increased in proportion to the degree of obesity , However, only plasma levels of estrone had a significant correlation with CT-derived abdominal visceral fat and femoral areas Since the increased metabolism of testosterone to estradiol did not account for the major increase in estradiol production in obese men , it is probable that estradiol is secreted or is produced from the peripheral conversion of estrone, as observed in postmenopausal women.

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This work was supported by a grant from the SNUH Research Fund Number The funding organizations had no role in the design or conduct of the study; in the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

Department of Family Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea. Department of Internal Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea. Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, United States.

You can also search for this author in PubMed Google Scholar. Study concept and design: D. and H. Acquisition of data: H. and D. Analysis and interpretation of data: D. and J. K Drafting of the manuscript: H.

Critical revision of the manuscript for important intellectual content: D. Statistical analysis: D. Obtaining funding: H. Study supervision: D. Correspondence to Donghee Kim. Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open Access This article is licensed under a Creative Commons Attribution 4. Reprints and permissions. Kwon, H. Body Fat Distribution and the Risk of Incident Metabolic Syndrome: A Longitudinal Cohort Study. Sci Rep 7 , Download citation.

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Skip to main content Thank you for visiting nature. nature scientific reports articles article. Download PDF. Subjects Metabolic syndrome Obesity. Abstract The effect of visceral adipose tissue VAT and subcutaneous adipose tissue SAT area on metabolic syndrome MS has been debated.

Results General characteristics of the study population As outlined in the Methods section, of the 5, subjects in the baseline cohort, 2, Full size table. Table 4 Incidence of each component of MS by the VAT and SAT areas at baseline. Discussion In this large prospective study, the VAT area was longitudinally associated with incident MS and its components during a 5-year follow-up period.

Methods Study subjects and design This longitudinal study was performed using a previously described cohort 8. Anthropometric and laboratory measurements The methods applied in this cohort have been described in detail elsewhere 8 , 35 , Measurement of abdominal adipose tissue Detailed descriptions of the methods used to measure the abdominal adipose tissue area have been published previously Statistical analysis The outcome of this study was the development of MS.

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Article PubMed Google Scholar Chung, S. Article CAS PubMed Google Scholar Grundy, S. Prolonged fasting is associated with a sharp drop in plasma leptin levels, which drives food intake While leptin is expressed in all adipose depots, including BAT, its expression is highest in subcutaneous WAT As one of the first adipokines discovered in the mids 87 — 90 , adiponectin is a well-described insulin-sensitizing hormone that impacts a wide range of tissues.

Adiponectin is a distinctly unique adipokine, as its expression and circulating levels are inversely proportional to adiposity levels, in stark contrast to leptin.

Adiponectin expression levels vary between sexes, with higher levels observed in females than males 91 — 93 , and between adipose tissue depots, with higher expression in subcutaneous than visceral WAT 94 , The insulin sensitivity-promoting properties of adiponectin are well-known, and are exemplified by the development of insulin resistance in adiponectin-deficient mice 96 , and the preservation of insulin sensitivity in adiponectin-overexpressing mice Adiponectin signals through two related receptors, ADIPOR1 and ADIPOR2, followed by docking of the adaptor protein APPL1 The resulting signaling pathway, mediated through peroxisome proliferator-activated receptor alpha PPARα , leads to metabolic improvements involving decreased hepatic gluconeogenesis, increased liver and skeletal muscle fatty acid oxidation, increased glucose uptake in skeletal muscle and WAT, and decreased WAT inflammation Thus, adiponectin receptors are highly expressed in skeletal muscle, liver, and adipose tissue.

In addition, adiponectin receptors are expressed in the pancreas, where adiponectin functions to mitigate β-cell loss by neutralizing inflammatory and lipotoxic ceramides and diacylglycerols In addition to β-cells, adiponectin has also been shown to exhibit strong anti-inflammatory effects on other cell types such as macrophages and fibrogenic cells 99 , , Taken together, adiponectin plays a protective role in mitigating features of the metabolic syndrome.

Resistin is a polypeptide that is secreted by obese adipose tissue. It was originally described as an adipocyte-specific hormone, but it is now thought to originate from macrophages residing in inflamed adipose tissue in mice and from circulating monocytes and tissue macrophages in humans , Evidence for this comes from an initial study in which it was observed that plasma resistin levels are elevated in a diet-induced obese mouse model, that blocking resistin action using a neutralizing antibody improves insulin sensitivity, and that recombinant resistin administration to healthy mice promotes insulin resistance These initial studies led to the suggestion that resistin plays an important role in modulating insulin resistance in the context of obesity, and it has been shown to correlate with insulin resistance in mice and humans Plasma resistin levels have been shown to be increased in obese animal models and humans — and to decrease with weight loss in humans Conversely, some studies have shown that adipose tissue-derived resistin is suppressed in obesity — , inciting the controversy over what role resistin plays in obesity that persists today.

Evidence suggests that visceral fat is the largest contributor to circulating resistin levels , supporting the case for an association between resistin and insulin resistance. Moreover, resistin is believed to be an active participant in propagating inflammatory responses.

Resistin can upregulate inflammatory cytokines such as TNFα and IL-6 in monocytes and macrophages in a nuclear factor kappa-B NFκB -dependent manner , and is positively associated with circulating inflammatory markers such as C-reactive protein CRP and TNFα Thus, while resistin is an established adipokine and has been shown in some cases to be associated with adverse health conditions such as obesity and insulin resistance, a clear role for resistin is still under active investigation.

Initially described as an adipokine secreted from omental WAT , it is now generally accepted that omentin is also expressed in other WAT depots such as epicardial fat, and that it derives specifically from the stromal vascular fraction of WAT , Omentin is a true endocrine hormone that circulates in the blood , Omentin levels are reduced in subjects with obesity and T2DM , , leading investigators to speculate that omentin may be involved in glucose homeostasis.

Indeed, studies using in vitro models showed that omentin enhances insulin-stimulated glucose uptake in human adipocytes by activating Akt signaling pathways , and studies in humans show a significant negative correlation between serum omentin levels as well as adipose omentin mRNA levels with insulin resistance , , Omentin levels have been shown to gradually increase in response to weight loss , Additional studies suggest that omentin has anti-inflammatory properties.

Omentin blunts cytokine expression in endothelial cells , vascular smooth muscle cells , , macrophages , cardiomyocytes , and adipose tissue itself , and is negatively associated with systemic inflammatory markers such as TNF and IL-6 Thus, omentin is considered to be a biomarker for metabolic health that may function to blunt obesity-related cytokine effects FGF21 is an endocrine hormone that is involved in the regulation of lipid, glucose, and energy homeostasis FGF21 has received a lot of attention for its insulin-sensitizing and weight loss-inducing effects when administered pharmacologically The liver is the primary source of circulating FGF21, induced by metabolically stressful conditions such as fasting, a ketogenic diet, protein restriction, and bariatric surgery , while the brain and adipose tissue are primary FGF21 targets , Other tissues are known to also secrete FGF21, including the pancreas and skeletal muscle , However, under certain metabolic conditions such as obesity, WAT and BAT may also produce FGF21 This is supported by several studies showing that BMI and adiposity positively correlate with circulating FGF21 levels in mice and humans — It is clear that FGF21 levels become elevated as obesity develops in mice and humans, and are positively correlated with BMI, adiposity, and FGF21 expression levels in adipose tissue — While many studies have shown that adipose tissue expresses FGF21 in rodents , — , there is still some debate about whether FGF21 is readily expressed in human adipose tissue.

There are a handful of studies that suggest that adipose tissue FGF21 mRNA expression is below detection levels or not expressed by adipose tissue However, numerous additional studies have found detectable FGF21 mRNA expression in visceral WAT , , subcutaneous WAT , , , epicardial WAT , cervical adipose tissue , , and PVAT , , with the latter two depots containing both WAT and BAT.

FGF21 protein has also been detected in adipose tissue by Western blot and immunohistochemistry Some studies suggest that adipose-derived FGF21 is a marker of metabolic stress, as it has been shown to correlate with features of the metabolic syndrome , , Regardless, a clearly-defined function of adipose-derived FGF21 has not yet been established, nor whether adipose-derived FGF21 promotes primarily local effects or contributes to the circulating FGF21 pool under particular metabolic conditions.

Elegant studies using tissue-specific Fgf21 KO mice show that adipocyte-derived Fgf21 is not involved in obesity-associated insulin resistance, and that adipose-derived Fgf21 doesn't circulate, instead acting in a paracrine fashion However, the mice used in that study were fasted for 24 h, introducing a metabolic stress that would likely only induce liver-derived Fgf21 that may have masked any contribution from adipose-derived Fgf In later studies, a thermogenic role for adipose-derived Fgf21 has been described, in which the browning of WAT was shown to require adipocyte-Fgf21 , Thus, it is possible that hepatic- and adipose-derived FGF21 are induced by different stimuli, and that more studies are required to conclusively define a role for adipose-derived FGF Obesity results when energy intake chronically exceeds energy expenditure.

Many factors are involved, including genetic, epigenetic, hormonal, and lifestyle factors that are beyond the scope of this review. Adipocyte number is believed to be tightly regulated and determined during childhood However, during the development of obesity, adipose tissue can expand by either hypertrophy an increase in adipocyte size or hyperplasia an increase in adipocyte number due to the recruitment of new adipocytes.

Obesity is characterized by dysfunctional adipose tissue, in which adipocytes initially become hypertrophic during periods of caloric excess and secrete adipokines that result in the recruitment of additional pre-adipocytes, which differentiate into mature adipocytes as compensatory protection against some of the adverse metabolic consequences of obesity This concept is supported by observations in AdipoChaser mice, a model for tracking adipogenesis AdipoChaser mice fed a high fat diet display evidence of hypertrophy of visceral WAT within 1 month, while hyperplasia occurs after 2 months.

Importantly, subcutaneous WAT does not undergo hyperplasia, and hypertrophy lags behind the visceral compartment, with evidence of subcutaneous WAT hypertrophy after 2 months of high fat feeding However, when the capacity for adipocyte recruitment and hypertrophy is overwhelmed, fat accumulates in ectopic sites such as visceral depots, the liver, skeletal muscle, and pancreatic beta cells.

These changes are accompanied by inflammation, insulin resistance and other features of the metabolic syndrome, and have been termed metabolically unhealthy obesity MUHO , In contrast to MUHO, some people accumulate fat mainly in subcutaneous depots, a condition that has been termed metabolically healthy obesity MHO.

MHO is not accompanied to any great extent by insulin resistance, adipose tissue and systemic inflammation, and other features of the metabolic syndrome such as dyslipidemia and hypertension — Thus, the distribution of fat accumulation is a major determinant of metabolic complications associated with obesity, which can increase the risk of CVD.

Various features that contribute to dysfunctional WAT in obesity will be discussed in the sections that follow. A sub-group of obese individuals remain insulin-sensitive, and exhibit normal metabolic and hormonal profiles despite having a BMI that would characterize them as obese , Therefore, MHO individuals have a lower risk for developing T2DM and cardiovascular disease MHO is sometimes defined as having 2 or less features of the metabolic syndrome or based on homeostatic model assessment of insulin resistance HOMA-IR measures, but consensus on a precise definition does not exist Thus, some individuals classified as having MHO rather fall somewhere between metabolically healthy and unhealthy.

Moreover, individuals with so-called MHO can progress to develop features of the metabolic syndrome with time — Because CVD outcomes in general relate to the number of metabolic abnormalities present in individuals with MUHO — , there is less CVD in individuals with MHO than those with the metabolic syndrome.

In addition, while MHO individuals are so defined due to a healthier cardiometabolic profile than those with MUHO, the true clinical benefits of MHO remain in question, as the cardiometabolic profile and insulin sensitivity of MHO individuals typically does not improve significantly with weight loss , — Nevertheless, evidence from animal models and cultured adipocytes do suggest that the preservation of the capacity for subcutaneous WAT expansion mitigates extensive visceral and hepatic fat accumulation, potentially driving the MHO phenotype 76 , 97 , Other obese individuals tend to accumulate fat mainly intra-abdominally in visceral depots, which is also known as central obesity.

Visceral adiposity is associated with insulin resistance, a predisposition to diabetes, local and systemic inflammation, dyslipidemia [characterized by hypertriglyceridemia, a preponderance of small, dense low-density lipoprotein LDL particles and reduced high-density lipoprotein HDL -cholesterol levels], insulin resistance, dysglycemia [a broad term that refers to an abnormality in blood sugar stability], adipose tissue and systemic inflammation, hypertension, a thrombogenic profile and non-alcoholic fatty liver disease NAFLD This constellation of CVD risk factors associated with visceral obesity is widely known as the metabolic syndrome and is a hallmark of MUHO, illustrated in Figure 1.

Visceral obesity and the metabolic syndrome are associated with an increased risk of developing CVD, which is exacerbated when overt diabetes develops as a result of insulin secretion failing to adequately compensate for insulin resistance. Interestingly, even normal weight individuals who accumulate fat intra-abdominally have these metabolic abnormalities , , including an increased risk of CVD.

Asians and Asian-Americans are particularly prone to accumulate intra-abdominal fat and have features of the metabolic syndrome despite having normal weights and BMI values by Western standards , raising the question of whether different normal values should apply to individuals of Asian ancestry.

These indexes are notable for their inclusion of upper subcutaneous WAT, which some consider to contribute as much, if not more, to metabolic syndrome than visceral WAT alone CT scanning at the level of the umbilicus has been found to be useful but is expensive and not practical other than for research purposes at present.

Lower body subcutaneous WAT does not correlate with risk factors for the metabolic syndrome, potentially due to a slower FFA turnover, higher levels of adipocyte hyperplasia, and lower levels of inflammation — Figure 1. Metabolically healthy obesity MHO vs. metabolically unhealthy obesity MUHO.

In comparison with lean metabolically healthy subjects, those with MHO have increased adiposity and BMI, but with reduced systemic inflammation and retained insulin sensitivity, thus defining them as not having metabolic syndrome MetS.

MHO subjects have elevated subcutaneous white adipose tissue WAT levels, without excessive accumulation of visceral fat. Their adipokine profile is similar to lean subjects, but with increased leptin, resistin, and FGF21, and decreased adiponectin, which limits their risk of developing type 2 diabetes mellitus T2DM and cardiovascular disease CVD in the short term.

By contrast, those with MUHO exhibit elevated insulin resistance and systemic inflammation in addition to increased adiposity and BMI over lean controls, contributing to MetS. MUHO individuals have excess subcutaneous and intra-abdominal adipose tissue, with increased hepatic fat and fat distributed amongst other visceral organs.

This leads to a dysfunctional adipokine profile, characterized by reduced adiponectin and omentin, with further elevated leptin, resistin, FGF21, and cytokines when compared to lean controls. Thus, MUHO subjects are at risk for developing T2DM and CVD.

Notable differences in the adipokine profile between MHO and MUHO subjects have been reported, which could contribute to their respective risks for T2DM and CVD. Leptin has been shown to be higher in MUHO than MHO obese Chinese children in one study , but was not found to differ between adult groups in several other studies — By contrast, adiponectin has consistently been shown to be higher in subjects with MHO than in those with MUHO, despite both populations having lower adiponectin than metabolically healthy lean controls , — Resistin and FGF21 levels tend to be highest in the MUHO population , Data on whether omentin levels differ between MHO and MUHO has been inconsistent, with one study suggesting that MUHO subjects have higher omentin levels than MHO subjects , and other suggesting the opposite, that omentin levels are negatively correlated with the metabolic syndrome , Cytokines such as TNFα and IL-6 as well as the chemokines SAA and MCP-1 have been shown to be elevated in MUHO These adipokine differences between subjects with MHO and MUHO are depicted in Figure 1.

Adipose tissue expansion in obesity is accompanied by inflammatory changes within adipose tissue, contributing to chronic low-grade systemic inflammation that is characterized as mildly elevated levels of circulating cytokines, chemokines, and acute phase reactants.

Expansion of adipose tissue depots during weight gain is accompanied by an infiltration of new inflammatory cells, the major one initially being macrophages. These pro-inflammatory cells are recruited in response to chemokines such as monocyte chemotactic protein-1 MCP-1 produced by hypertrophic adipocytes , Studies in mice have demonstrated that most macrophages in obese adipose tissue are derived from circulating monocytes , although a small percentage appear to derive from proliferation of resident tissue macrophages These anti-inflammatory macrophages are believed to be responsible for maintaining tissue homeostasis It remains unclear whether the derivation of adipose tissue macrophages is the same in human obesity.

Macrophage accumulation occurs to a greater extent in visceral than in subcutaneous adipose depots in both rodents and humans — Macrophages are seen in crown-like clusters, where they are thought to represent an immune response to dead and dying adipocytes However, use of genetic markers show that these cells have significant differences from classical M1 macrophages and alternate nomenclatures have been suggested for these pro-inflammatory cells.

Morris and Lumeng have divided adipose tissue macrophages into several populations based on cell surface markers and expression profiling Using a proteomics approach, Kratz et al. showed that markers of classical activation were absent on ATMs from obese humans.

Such markers of metabolic activation were expressed by pro-inflammatory macrophages in adipose tissue from obese humans and mice and correlated with the extent of adiposity In addition to macrophages, T-cells also are present in normal adipose tissue and demonstrate phenotypic change during weight gain.

Th2 cytokines e. With weight gain in mice there is a shift away from a predominance of TH2 T cells present in lean adipose tissue and toward more TH1 and cytotoxic T cells as well as a reduction in regulatory T cells Tregs Interferon γ IFNγ —expressing Th1 polarized T cells appear to promote adipose tissue inflammation and increased IFN-γ activity has been reported in adipose tissue in both mice and humans , A subset of T cells called natural killer T NKT cells respond to lipid or glycolipid antigens — The number of invariant NKT iNKT numbers has been observed to be reduced in adipose tissue and livers from obese mice and humans — B-cells and mast cells also are increased in adipose tissue in the obese state , , Use of specific cell surface markers has also demonstrated the presence of dendritic cells in adipose tissue, and studies indicate that dendritic cells are independent contributors to adipose tissue inflammation during obesity , There is good evidence to support the notion that the systemic inflammation that is associated with obesity and contributes to insulin resistance begins with adipose tissue inflammation.

The regulation of hepatic C-reactive protein CRP and serum amyloid A SAA is likely in response to IL-6 secretion from visceral adipose tissue that directly targets the liver via the portal circulation — CRP is a prominent biomarker for insulin resistance and CVD — , and SAA antagonizes insulin action in adipocytes, thus contributing to systemic insulin resistance SAA also has been associated with CVD in some rodent and human models , — In summary, the discovery of elevated secretion of inflammatory cytokines by obese adipose tissue provides evidence that obesity directly mediates systemic inflammation, which contributes to insulin resistance and CVD discussed further in later sections.

Obesity is associated with elevated circulating levels of IL-6 and TNFα, which are subsequently decreased with weight loss , Adipose tissue is a major source of these cytokines as well as the chemokine MCP-1, which is important for recruitment of inflammatory cells such as macrophages to expanding adipose tissue While such inflammatory mediators that originate from adipose tissue could technically be classified as adipokines, they are also produced by the majority of cell types in the body and will therefore be described in further detail in this section.

It should be noted that cytokine and chemokine production is limited in lean adipose tissue and in subjects with MHO.

Many cell types synthesize and secrete these cytokines and chemokines, including several that make up the adipose tissue milieu such as monocytes, macrophages, dendritic cells, B cells, and T cells.

As such, they play a prominent role in adipose tissue pathophysiology associated with obesity. Much research has been devoted to the role that adipose-derived IL-6 plays in the etiology of obesity. The expansion of adipose tissue is accompanied by excessive adipocyte lipolysis and subsequently elevated FFA levels, which promotes adipocyte IL-6 secretion , Omental fat produces 2 to 3-fold higher levels of IL-6 than subcutaneous fat , providing a potential mechanism for the higher contribution of omental WAT to insulin resistance Most studies in vitro and in mice suggest that adipose-derived IL-6 promotes hepatic insulin resistance and glucose intolerance , , , while some indicate that in certain contexts IL-6 signaling in WAT and liver may be protective against metabolic disease , For example, mice with genetic disruption of the IL-6 receptor specifically in the liver exhibit exacerbated hepatic inflammation and impaired glucose tolerance , suggesting that IL-6 may also function to limit hepatic inflammation.

Thus, the context in which IL-6 signaling is studied is critically important for the interpretation of its function. In addition to its secretion from inflammatory cells such as monocytes and macrophages, TNFα was first described as an adipokine in As with IL-6, TNFα levels positively correlate with adiposity, BMI, insulin levels, and insulin resistance , While adipocytes themselves can secrete TNFα, the majority of TNFα secreted from adipose tissue is derived from immune cells in the stromal vascular fraction, and that obesity-associated increases in TNFα largely reflect the infiltration of pro-inflammatory macrophages within expending adipose tissue One mechanism by which adipose-derived TNFα may promote insulin resistance is by directly activating hormone sensitive lipase HSL , thereby increasing FFA release from adipocytes which promotes insulin resistance in the liver and skeletal muscle Another mechanism is via autocrine activation of insulin receptor substrate-1 IRS-1 , which prevents insulin from interacting with its receptor Monocyte chemotactic protein-1 MCP-1 is a potent chemotactic factor that promotes monocyte and macrophage recruitment into sites of inflammation during tissue injury and infection.

It is secreted by adipocytes during the development of obesity and leads to infiltration of monocytes, which differentiate to become adipose tissue macrophages. The macrophages in turn secrete additional MCP-1 leading to further recruitment of inflammatory cells , Body mass index and adiposity strongly correlate with adipose CCL2 the gene encoding MCP-1 expression levels, and MCP-1 decreases following weight loss in humans In addition, mice engineered to express elevated levels of Ccl2 specifically from adipocytes exhibit increased macrophage recruitment into adipose tissue, and subsequently increased insulin resistance, effects that were not observed in diet-induced obese mice that were deficient in Ccl2 Evidence suggests that human visceral WAT secretes higher levels of MCP-1 than subcutaneous WAT These studies and others have prompted the suggestion that MCP-1 could be a viable therapeutic target for the treatment of obesity and associated insulin resistance.

While well-described as an acute phase protein secreted by the liver in response to pro-inflammatory cytokines, SAA is also expressed in adipocytes and macrophages and correlates with adiposity , — There are 4 subtypes of SAA: SAA1—4.

SAA1 and SAA2 are highly upregulated in response to inflammation, while SAA4 is largely constitutively expressed. SAA3 is a pseudogene in humans, replaced by SAA1 and SAA2 in extra-hepatic tissues. While the best defined cell source of SAA1 and SAA2 is hepatocytes, SAA1 and SAA2 are also expressed from adipocytes and macrophages under inflammatory conditions in metabolic diseases such as obesity, insulin resistance, and cardiovascular disease SAA3 expression is increased during hypertrophy of cultured mouse adipocytes and in gonadal fat in obese mice , Inducible forms of SAA also are expressed in both subcutaneous and omental WAT from obese humans.

Thus, the increased adipocyte size and number that accompanies obesity is also associated with elevated adipose tissue-derived SAA levels, likely in part due to increased hepatic secretion in response to cytokines produced in adipose tissue.

In obesity, white adipose tissue may become dysfunctional and unable to properly expand to store excess ingested energy, triggering storage of triglycerides in sites where the primary function is not fat storage.

Excessive amounts of visceral fat also is considered to be a form of ectopic fat, and as noted earlier, is associated with features of the metabolic syndrome and an increased risk of T2DM and cardiovascular complications In animal models as well as in humans, it has been shown that the accumulation of lipotoxic diacylglycerols DAGs and ceramide, as occurs with visceral obesity, leads to impaired insulin signaling and reduced glucose uptake in skeletal muscle and liver — More specific mechanisms by which ectopic fat accumulation in particular tissues promotes insulin resistance will be explained in the following sections.

Several studies have reported an inverse relationship between hepatic lipid content and whole-body insulin sensitivity — The liver is a major target for the excessively produced inflammatory cytokines and FFAs released from obese WAT see later.

FFA-derived triglycerides accumulate in the cytoplasm of hepatocytes in the form of lipid droplets. While the lipid droplets may not be lipotoxic per se , various intermediate lipid moieties generated during triglyceride synthesis e.

Selective upregulation of ceramide degradation pathways in the liver has been shown to reverse hepatic lipid accumulation and improve glucose tolerance in diet-induced obese mice Moreover, obesity-associated reductions in adiponectin have also been shown to contribute to hepatic steatosis, presumably by blunting hepatic fatty acid oxidation, a process regulated by adiponectin — It also has been suggested that adipose tissue inflammation contributes to hepatic lipid accumulation.

Kanda et al. showed that overexpressing Ccl2 from adipocytes in mice led to macrophage accumulation in adipose tissue and subsequent hepatic steatosis and hepatic insulin resistance, without an obese phenotype Similarly, mice in which Ccl2 had been deleted showed resistance to high fat diet-induced insulin resistance and hepatic steatosis, an effect that was accompanied by reduced expression of TNFα in adipose tissue Additional evidence to support the notion that adipose tissue inflammation promotes hepatic steatosis derives from studies showing that adipose-derived cytokines promote lipolysis of WAT stores , , thus increasing circulating FFA levels.

In the healthy liver, the role of Kupffer cells is to phagocytose pathogens and toxins and to maintain tissue homeostasis and repair, akin to an M2 macrophage , The primary stimuli for Kupffer cell activation likely derive from dysfunctional adipose tissue, including FFA, cytokines, and adipokines Adipokine imbalance such as the hypoadiponectinemia that results from visceral adipose tissue expansion fails to suppress hepatic inflammation and oxidative stress, contributing to Kupffer cell activation.

Thus, signals from dysfunctional obese adipose tissue propagate hepatic inflammation by activating resident Kupffer cells, which then themselves secrete pro-inflammatory cytokines, further amplifying systemic inflammation Lipids also can be stored within skeletal muscle when the capacity for fat storage by WAT is exceeded Lipids can be stored either between muscle fibers as adipocytes, or extramyocellular lipids , or within muscle cells cytosolic triglycerides, or intramyocellular lipids Pre-adipocytes have been identified within skeletal muscle, providing evidence that distinct adipocyte cells may reside between skeletal muscle fibers There is an association between ectopic skeletal muscle fat and insulin resistance that is largely dependent on BMI, but this association persists when BMI is statistically accounted for — It remains to be determined whether skeletal muscle fat is simply a marker of metabolic dysfunction or if it plays an active role in mediating insulin resistance.

Ectopic skeletal muscle fat, as with ectopic fat in other areas, has the potential to impair insulin action in skeletal muscle through the inhibition of insulin signaling by lipotoxic DAGs and ceramide , Several large clinical trials including SECRET and CARDIA have recently suggested that skeletal muscle fat could play a direct role in increasing cardiometabolic risk — However, while ectopic fat in skeletal muscles is often associated with metabolic disease, highly trained athletes have been reported to have comparable amounts of skeletal muscle fat as subjects with T2DM, yet their tissue remains highly insulin sensitive Obesity and T2DM are both independently associated with fat accumulation in the heart , rendering ectopic fat in the heart as a strong predictor of CVD , , particularly in subjects with T2DM Similar to the liver, excess circulating FFA can also lead to increased triglyceride deposition in the heart.

Cardiac tissue mainly utilizes FFA for metabolism, but when delivered in excess of basal myocardial fatty acid oxidation rates can also lead to the accumulation of lipotoxic products In addition to ectopic cardiac myocyte lipid storage, excess FFA can be stored in epiWAT, pericardial fat between the visceral and parietal pericardia , or PVAT PVAT in particular has a major impact on vascular homeostasis.

As a source of several vasoactive mediators, PVAT influences vascular contractility. Healthy PVAT is thought to be a largely anti-inflammatory tissue , with characteristics akin to BAT in the areas surrounding the thoracic aorta in particular However, in the setting of obesity, dysfunctional PVAT releases predominantly vasoconstrictive and proinflammatory mediators that negatively influence vascular homeostasis — Similarly, epiWAT is a source of bioactive molecules that negatively impact cardiac rhythm and perpetuate an atherogenic environment in obesity Patients with T2DM express higher levels of the LDL and very low-density lipoprotein VLDL receptors in epiWAT than non-diabetic control subjects , suggesting that altered lipid metabolism in epiWAT could be associated with T2DM.

Recent studies have connected ectopic pancreatic fat with β-cell dysfunction and T2DM — , which in turn is associated with an increased risk of CVD. Therefore, lipotoxic lipid intermediates may also play a role in increasing the risk of CVD by elevating levels of pancreatic fat, thus leading to T2DM In contrast to skeletal muscle, ectopic pancreatic fat is characterized mostly by adipocyte infiltration rather than intracellular lipid accumulation The accumulation of fat in the pancreas also has been reported to accelerate acute pancreatitis due to increased levels of lipolysis and inflammation , Compared with healthy lean controls, obese subjects display reduced BAT content, identified as tissue that actively takes up 2-[ 18 F]fluorodeoxyglucose FDG This reduction in active BAT mass appears to be more prevalent in visceral obesity , Concurrently, individuals with detectable BAT activity display lower blood glucose, triglyceride and FFA levels, lower glycated hemoglobin Hb1Ac levels, and higher HDL cholesterol levels than people with no detectable BAT , Thus, loss of BAT function in association with obesity could contribute to the development of insulin resistance and hyperlipidemia.

It has been shown that while cold exposure can activate BAT to a certain degree in obese subjects and those with T2DM, the levels of BAT activation achieved are substantially lower than in healthy lean subjects , While BAT is largely resistant to the development of mild obesity-induced local inflammation, BAT inflammation becomes quite pronounced with stronger obesogenic insults Such inflammation can directly upset the thermogenic potential of BAT by impairing its ability to take up glucose described in more detail in later sections , Whether individuals who inherently possess less active BAT are more prone to obesity and facets of the metabolic syndrome or whether these pathological conditions themselves reduce BAT activity requires further investigation.

Regardless, it is still widely believed that strategies that augment BAT or beige activity could represent viable therapeutics to combat metabolic syndrome , Efforts to enhance BAT activation in humans consist of intermittent regular cold exposure, introduction of β 3 -adrenergic receptor agonists, and exercise 29 , However, robust reductions in body weight in humans have not yet been shown to be clinically significant when BAT is activated , necessitating further mechanistic studies to elucidate whether BAT activation is a viable target for metabolic improvement in humans.

Whether BAT undergoes similar immune cell changes as WAT under obesogenic conditions is still not clear. Such BAT inflammation reportedly lowers the thermogenic potential of this tissue , presumably due to increased local insulin resistance , , which could reduce the glucose and fatty acid oxidizing capacity of BAT.

Similar to BAT, beige adipocyte quantity and functionality appear to be sensitive to local inflammation. A study in which IkB kinase IKK, an enzyme that is required for NFκB activation and subsequent inflammatory cytokine transcription was inactivated in mice, not only blunted adipose tissue inflammation and body weight gain, but enhanced WAT browning Similarly, inhibiting a major intracellular mediator of toll-like receptor 4 TLR4 signaling, interferon regulatory factor 3 IRF3 , blunted WAT inflammation and augmented WAT browning Thus, accumulating evidence suggests that obesity-associated inflammation hinders the thermogenic and insulin sensitizing effects of both BAT and beige adipocytes.

Abundant evidence indicates that adiposity and adipose tissue inflammation are associated with insulin resistance, which refers to a reduced response to binding of insulin to its receptor in peripheral tissues such as adipose tissue and skeletal muscle.

This differs from glucose effectiveness, which is uptake of glucose by peripheral tissues in an insulin-independent manner.

Insulin inhibits hepatic glucose output and stimulates lipogenesis in the liver, both of which are reduced in the presence of insulin resistance. Such desensitization of insulin signaling pathways also inhibits glucose uptake in peripheral tissues and stimulates lipolysis in adipose tissue.

To compensate for reduced insulin sensitivity, insulin secretion is increased in order to maintain euglycemia. If the pancreatic beta cells are unable to secrete sufficient insulin to compensate for the reduced insulin sensitivity termed beta cell dysfunction , hyperglycemia will ensue, leading to glucose intolerance and eventually T2DM While the precise mechanisms that lead to beta cell dysfunction are not completely understood, ectopic fat accumulation may contribute, as discussed earlier.

Nonetheless, ample evidence suggests that excess adiposity and adipose tissue inflammation contribute to insulin resistance [reviewed in 64 , ]. Many studies have demonstrated that excess adiposity is correlated with insulin resistance in humans. Cross-sectional studies in men of European, Asian Indian, and American descent have shown that total, visceral, and subcutaneous adiposity, BMI, and waist circumference are all negatively associated with insulin sensitivity , As noted earlier, adiposity, especially visceral adiposity, is characterized by adipose tissue inflammation.

Several hypotheses have been put forth to account for the relationship between adipose tissue inflammation and insulin resistance. These include production of pro-inflammatory cytokines by adipocytes and adipose tissue macrophages discussed previously in the section on WAT Inflammation , excess FFA, decreased adiponectin, increased resistin and retinol binding protein, ceramide accumulation, and ectopic fat accumulation in liver and skeletal muscle It has been shown that adipose tissue mass correlates with circulating FFA in obese humans, with a tendency for individuals with visceral adiposity to have higher FFA turnover — It has also been reported that individuals with T2DM tend to have elevated FFA levels over non-diabetic controls , an effect found to correlate more strongly with insulin sensitivity rather than obesity Consistent with this, one study reported that FFA levels were lower in MHO subjects than those with MUHO In addition to dysregulated energy metabolism, disruption of the endocrine function of obese adipose tissue has now been shown to contribute to insulin resistance, described in more detail below.

Adipocytes in obesity simultaneously secrete lower levels of adiponectin and elevated levels of cytokines and chemokines, such as TNFα, IL-6, MCP-1, and SAA. Not only is there evidence that such inflammatory cytokines contribute directly to insulin resistance in hepatocytes and myocytes , they also directly inhibit adiponectin production from adipocytes There is evidence that hypoadiponectinemia plays a role in obesity-associated T2DM — Subjects with T2DM exhibit reduced circulating adiponectin levels , ; similarly, MHO subjects have higher circulating adiponectin than those with MUHO This may be explained by the nature of adipose tissue expansion in these transgenic mice, which had smaller, less inflamed adipocytes and less liver fat content.

As discussed in earlier sections, FGF21 is a hormone produced by the liver as well as adipocytes that exerts insulin-sensitizing effects.

However, recent evidence has paradoxically suggested an association between serum FGF21 levels and obesity-associated metabolic syndrome , FGF21 levels have been reported to be 2-fold higher in MUHO when compared to MHO Moreover, subjects with T2DM were reported to have significantly higher plasma levels of FGF21 than insulin-sensitive controls, with FGF21 levels positively correlated with BMI, HOMA-IR, and Matsuda index, suggesting a strong correlation with insulin resistance Plasma FGF21 levels also correlated strongly with visceral, epicardial, hepatic, and skeletal muscle ectopic fat levels, measured using slice multidetector CT scanning This conclusion was reached based on some observations that circulating FGF21 levels are increased in obesity, with lower FGF21 receptor expression levels on target tissues such as adipose tissue , However, this notion has been challenged by evidence that obese subjects are equally responsive to pharmacological administration of FGF21 , Thus, it has now been proposed that obesity-associated FGF21 is increased as a compensatory mechanism to preserve insulin sensitivity As such, a clear role for adipocyte-derived FGF21 in obesity and associated metabolic syndrome is still lacking.

Evidence suggests that ineffective adipose expansion promotes local inflammation and an insulin resistant phenotype However, sufficient adipogenesis and hyperplasia i.

Thus, strategies to increase the recruitment of adipocyte progenitor cells to expand adipose tissue by increasing adipose cell numbers could be protective against the metabolic consequences of obesity. A key structural and functional component of adipose tissue is made up of extracellular matrix ECM molecules, including collagen and proteoglycans such as versican and biglycan, among others Adipose tissue makes large quantities of ECM during active remodeling, as would occur during WAT expansion in obesity — To date, most studies of WAT ECM function have centered around collagen, which can form a scaffold that constrains adipocyte expansion due to mechanical stress , , Targeting ECM components to release adipocytes from such constraints due to excessive ECM production could potentially alleviate the ectopic accumulation of fat that drives the metabolic syndrome.

While the majority of adipose tissue in humans is localized subcutaneously , the volume of visceral adipose tissue is believed to be a strong predictor of insulin resistance , independent from subcutaneous fat quantity , The association between insulin resistance and visceral adipose mass is particularly striking in certain ethnic populations, with T2DM rates of While visceral adiposity is positively associated with insulin resistance, there is evidence to suggest that it may not be a causal factor.

Other conditions associated with visceral adiposity, such as hepatic fat content, may instead drive insulin resistance , Some clinical studies have dissociated the glucose metabolic effects of visceral adiposity from hepatic lipid accumulation.

In one such study, significant differences in insulin sensitivity in the liver, skeletal muscle, and adipose tissue were reported in obese human subjects who differed in hepatic lipid content, with no such differences observed in obese subjects who differed in visceral adiposity Similarly, in a study in which obese subjects were matched for liver fat content, no differences in indices of glucose metabolism were noted Insulin-sensitive MHO individuals tend to have lower visceral and intrahepatic fat accumulation than their MUHO counterparts , , , providing further evidence that these fat depots contribute to insulin resistance.

Collectively, while visceral adiposity and hepatic fat content are both strongly associated with whole-body and tissue-specific insulin resistance, hepatic lipid accumulation may play a more direct role in negatively modulating glucose homeostasis.

Many studies have suggested that fat distribution is strongly associated with insulin resistance, with visceral adiposity being the strongest predictor of insulin resistance , , While the detrimental effects of visceral and hepatic lipid accumulation on glucose metabolism are clear, it is also becoming increasingly appreciated that lower body subcutaneous adiposity may be metabolically protective — Large-volume liposuction of subcutaneous WAT has shown little to no metabolic benefit in human trials Gluteofemoral adipose mass is positively associated with insulin sensitivity in humans, coupled with a slower rate of lipolysis and subsequent FFA release, lower levels of inflammatory cells and cytokines, and elevated adipokines such as leptin and adiponectin Evidence from animal models has suggested that transplantation of subcutaneous WAT into the visceral cavity of recipient mice promotes less body weight and adiposity gain than transplantation with visceral WAT, resulting in greater insulin sensitivity in the liver and endogenous WAT Taken together, a growing body of evidence suggests that adipose tissue and ectopic lipid distribution contribute to whole-body glucose homeostasis.

With the purported potential to improve glucose homeostasis, interest in BAT and beige adipose tissue as therapeutic targets has increased in recent years. Studies in rodents in which BAT is transplanted into diseased mouse models have shown that transplanted BAT improves insulin sensitivity, glucose metabolism, and obesity — , likely mediated by batokine effects.

As a highly metabolically active organ, BAT contributes to glucose clearance by taking up relatively large amounts of glucose from the circulation, thus reducing insulin secretion by pancreatic β-cells Indeed, individuals that possess detectable BAT have lower fasting glucose concentrations than those without active BAT Glucose disposal through activated BAT occurs by both insulin-dependent and insulin-independent mechanisms For example, the cold exposure-mediated influx of glucose into active BAT has been suggested to be an insulin-independent process — However, as the insulin receptor is highly expressed in BAT tissue, it is considered to be one of the most sensitive insulin target tissues and thus an important organ for glucose disposal BAT activation further enhances insulin signaling in BAT itself by augmenting insulin-independent glucose uptake associated with thermogenesis and glucose uptake due to insulin signaling.

Thus, strategies that activate BAT and beige adipose tissue have the capacity to improve insulin resistance by clearing excess glucose — Several pathologic conditions, including hypercholesterolemia and systemic inflammation, are hypothesized to drive atherosclerotic CVD.

With a primary function of sequestering lipotoxic lipids and the known potential for chronic inflammation, obese adipose tissue has emerged as a potential player in the regulation of these atherogenic factors.

Obesity has been officially classified as an independent risk factor for CVD by the American Heart Association since , meaning that obesity treatment is likely to lower the incidence of CVD As alluded to in previous sections, people with MHO are at a lower risk of experiencing cardiovascular events than people with MUHO , yet those without obesity are at a considerably lower risk for future events.

Thus, even a moderate level of weight loss, if sustainable, could potentially lower the risk of adverse CVD events Possible reasons include confounding factors such as smoking and the presence of co-morbidities that are associated with lower body weights, or the use of BMI rather than measures of visceral obesity for most studies on the obesity paradox.

Despite the obesity paradox in those with established CVD, the following sections will provide information regarding potential links between obesity T2DM and CVD.

The various features of adipose tissue depots, including ectopic fat, and how they contribute to T2DM and CVD are summarized in Figure 2. Notably, there are many similarities between adipose depot characteristics that contribute to both T2DM and CVD. Figure 2. Adipose depots and ectopic fat sites and their features that contribute to type 2 diabetes mellitus T2DM or cardiovascular disease CVD.

Features of intra-abdominal white adipose tissue WAT , subcutaneous fat, hepatic fat, heart and arterial fat inclusive of epicardial, pericardial, and perivascular fat , pancreatic fat, skeletal muscle fat, brown adipose tissue, and a dysbiotic gut that contribute to either T2DM or CVD.

Arrows indicate changes in comparison with subjects without T2DM or CVD. The accumulation of visceral fat in obesity is associated with the metabolic syndrome, its associated CVD risk factors, and an increased risk for clinical CVD This distribution of WAT has been shown to have the greatest effect on CVD risk and mortality among patients with normal body weight The risk of CVD in the metabolic syndrome has been considered to result from the presence of multiple CVD risk factors such as dyslipidemia hypertriglyceridemia, an excess of small, dense LDL particles and reduced HDL-cholesterol levels , hypertension, dysglycemia, and a thrombogenic profile that have been reviewed elsewhere — However, there are several additional potential mechanisms by which visceral WAT might contribute directly to CVD that involve FFA, insulin resistance, and inflammation.

Visceral WAT has higher lipolytic activity than subcutaneous WAT due to its having fewer insulin receptors, and thus is a significant source of FFA. Visceral-derived FFA can directly impact the liver via the portal vein, facilitating FFA uptake by the liver and subsequent hepatic insulin resistance.

Similarly, excess FFA from visceral fat might directly impair lipid metabolism and lead to dyslipidemia, which increases CVD risk. In obese diabetic subjects, plasma FFA levels have been shown to be elevated compared to BMI-matched non-diabetic subjects , supporting the notion that insulin resistance further elevates circulating FFA levels.

Moreover, the incidence of T2DM is nearly doubled in patients with the highest levels of FFA 90th percentile when compared with subjects with the lowest FFA levels 10th percentile In one study, obese T2DM subjects who had undergone overnight fasting during pharmacological inhibition of lipolysis exhibited improved insulin sensitivity and glucose tolerance , providing further evidence for an inhibitory effect of FFA on insulin sensitivity.

The adipokine profile of visceral WAT also contributes substantially to its association with CVD risk. Obese visceral WAT primarily secretes inflammatory cytokines such as resistin, TNFα, IL-6, IL-1β, MCP-1, and SAA, with reduced levels of adiponectin Plasma adiponectin levels are decreased in patients with CVD Adiponectin is believed to contribute to CVD protection by several mechanisms, including the reduction of lipid levels, repressing expression of inflammatory mediators such as VCAM, ICAM, E-selectin, TNFα, and IL-6, and by acting directly on the heart to improve ischemic injury by activating AMPK and subsequently increasing energy supply to the heart — Adiponectin also stimulates endothelial nitric oxide synthase eNOS , which maintains healthy vascular tone , Thereby, adiponectin would play a protective role in the development of CVD.

Conversely, leptin levels are positively associated with acute myocardial infarction, stroke, coronary heart disease, chronic heart failure, and left cardiac hypertrophy — , although the reasons for this remain largely unknown.

Leptin receptors are expressed in the heart, indicative of an important impact of direct leptin signaling Resistin is positively associated with systemic inflammatory markers , upregulates endothelial expression levels of VCAM-1 and endothelin-1 and promotes the proliferation of smooth muscle cells Resistin also associates positively with coronary artery calcification levels, and negatively with HDL cholesterol Thus, adipose-derived resistin levels could be used to predict the severity of coronary atherosclerosis Similarly, cytokines and chemokines such as those secreted from obese visceral WAT can induce expression of endothelial adhesion molecules , recruit macrophages , increase thrombosis , and reduce vasoreactivity , and are positively associated with cardiovascular events , While visceral WAT-derived cytokines are associated with these CVD-inducing processes, it is important to note that the direct contribution from visceral WAT is not currently known, as these are also secreted from other tissues.

As discussed in previous sections, in addition to cytokines and exclusive adipokines, WAT is also a source of FGF While the liver is considered to be the major source, adipocytes have also been shown to produce FGF21 to varying degrees in response to various stimuli.

In addition to its associations with obesity and T2DM, FGF21 levels have also been associated with increased risk for CVD — Subjects with CVD that also had diabetes exhibited even higher levels of FGF21 , suggesting an important role in diabetes-accelerated atherosclerosis.

In particular, FGF21 levels have been shown to positively correlate with hypertension and triglyceride levels, and to negatively correlate with HDL-cholesterol levels One study by Lee et al. suggested that plasma FGF21 levels are associated pericardial fat accumulation , which suggests that ectopic fat could be a source of FGF21 in metabolic disease.

Further studies are needed to discern whether adipocyte- or hepatic-derived FGF21 contribute to these effects. In stark contrast to these effects of physiological FGF21, pharmacological administration of FGF21 in humans and non-human primates reduces blood glucose, insulin, triglycerides, and LDL cholesterol, and increases HDL cholesterol , ,