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Pathogenic potential of adipose tissue and metabolic consequences of adipocyte hypertrophy and increased visceral adiposity Expert Rev. Cardiovasc. Ther. 6(3), 343–368 (2008)

Harold E Bays†, J Michael González-Campoy, George A Bray, Abbas E Kitabchi, Donald A Bergman, Alan Bruce Schorr, Helena W Rodbard and Robert R Henry †

Author for correspondence L-MARC Research Center, 3288 Illinois Avenue, Louisville, KY 40213, USA Tel.: +1 502 515 5672 Fax: +1 502 214 3999 [emailprotected]

When caloric intake exceeds caloric expenditure, the positive caloric balance and storage of energy in adipose tissue often causes adipocyte hypertrophy and visceral adipose tissue accumulation. These pathogenic anatomic abnormalities may incite metabolic and immune responses that promote Type 2 diabetes mellitus, hypertension and dyslipidemia. These are the most common metabolic diseases managed by clinicians and are all major cardiovascular disease risk factors. ‘Disease’ is traditionally characterized as anatomic and physiologic abnormalities of an organ or organ system that contributes to adverse health consequences. Using this definition, pathogenic adipose tissue is no less a disease than diseases of other body organs. This review describes the consequences of pathogenic fat cell hypertrophy and visceral adiposity, emphasizing the mechanistic contributions of genetic and environmental predispositions, adipogenesis, fat storage, free fatty acid metabolism, adipocyte factors and inflammation. Appreciating the full pathogenic potential of adipose tissue requires an integrated perspective, recognizing the importance of ‘cross-talk’ and interactions between adipose tissue and other body systems. Thus, the adverse metabolic consequences that accompany fat cell hypertrophy and visceral adiposity are best viewed as a pathologic partnership between the pathogenic potential adipose tissue and the inherited or acquired limitations and/or impairments of other body organs. A better understanding of the physiological and pathological interplay of pathogenic adipose tissue with other organs and organ systems may assist in developing better strategies in treating metabolic disease and reducing cardiovascular disease risk. KEYWORDS: adipocyte • adipose tissue • adiposopathy • obesity

Adipose tissue may be pathogenic through the adverse consequences of excessive fat mass alone, and/or through deleterious endocrinologic and immunologic activity. Adipocyte hypertrophy and visceral adipose tissue accumulation are associated with many of the most common metabolic diseases found in clinical practice, including Type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia and, possibly, atherosclerosis [1]. For the past 20–30 years, in the USA alone, the rate of overweight or obesity has increased as follows [401]: • Adults: increased from 15 to 33% • Children (2–5 years): increased from 5 to 14%

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• Children (6–11 years): increased from 7 to 19% • Adolescents (12–19 years): increased from 5 to 17% Since obesity and its metabolic consequences are now epidemics within many developed nations [2,3,402,403], it is important to understand the pathogenic potential of adipose tissue. The role of adipose tissue in human health is best considered within the context of its physiologic benefits versus its potential pathogenic contributions to ill health. A sole focus on fat mass is often inadequate in assessing the associated health risks of adipose tissue since being

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overweight alone is not necessarily detrimental. Modestly or moderately overweight patients may actually have decreased mortality from noncancerous, noncardiovascular disease (CVD) causes and no increased mortality due to cancer or CVD disease [4]. In addition, while obesity is associated with significantly increased CVD and obesity-related cancer mortality, and while combined overweight and obesity is associated with increased mortality from T2DM and kidney disease, comparisons across surveys suggest a decrease in the association of obesity with CVD mortality over time [4]. Overall, this suggests that excessive body fat is more closely associated with increased CVD risk when adipose tissue is pathogenic. Pathogenic adipose tissue may lead to major atherosclerotic coronary heart disease (CHD) risk factors, such as T2DM, hypertension and dyslipidemia, as well as to other more direct adverse effects upon the vasculature and heart [1]. Current obesity guidelines are often based upon body mass index (BMI) and waist circumference, with differing therapeutic cut-off points dependent upon the presence of comorbidities [404]. However, given that the increase in metabolic disease with increasing BMI is both continuous and gradual [5,6], specific cut-off points may not apply to individual patients, particularly when potential ethnic and gender variances are taken into consideration [7]. Another challenge is that despite its known medical, monetary and human costs [8], obesity (which includes many patients with pathogenic adipose tissue) has not yet been universally recognized as a disease [405]. ‘Disease’ can be defined as an impairment of body function or system, often accompanied by pathological alterations in tissues or cells, resulting in adverse clinical outcomes [9]. If adipocyte hypertrophy and visceral adipose tissue accumulation occur during positive caloric balance, then the pathogenic consequences may unfavorably affect other body organs, such as liver, muscle and pancreas, resulting in adverse clinical outcomes [6]. It is, therefore, through the understanding of the pathogenic potential of hypertrophied adipocytes and increased accumulation of visceral adipose tissue that helps support how an increase in body fat, in many individuals, is itself a disease. It also provides a framework for explaining why treating pathogenic adipose tissue is more rational than treating BMI alone [7]. Genetic & environmental considerations

The pathogenic potential of adipose tissue is dependent upon genetic predisposition and environmental surroundings. Many Native American groups, including the Pima Indians, are genetically predisposed to insulin resistance, obesity and the development of T2DM; obesity markedly increases the risk of T2DM [10]. Interestingly, the risk of CHD may not be increased [11,12]. Anatomically, the prevalence of T2DM in Pima Indians is increased in the presence of hypertrophic, bloated, pathogenic adipocytes, as opposed to smaller, leaner and more functional fat cells [13]. In fact, it is the presence of

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anatomically larger adipocytes that best predicts the onset of T2DM among Pima Indians, compared with the presence of obesity alone [14]. Additionally, the prevalence of T2DM in Mexican Pima Indians is no different than other, non-Pima Mexicans. But with the excessive body fat found in US Pima Indians, this better reveals their genetic predisposition towards developing metabolic disease. Thus, US Pima Indians, who are substantially more overweight than their leaner Mexican counterparts [10], have an approximately five-times greater prevalence of T2DM. Asians are another population illustrating the importance of genetics in predisposing patients to the adverse clinical consequences of pathogenic adipose tissue [15–19]. Asians have a high prevalence of T2DM, the metabolic syndrome and CHD. Particularly well described are individuals from the South Asian subcontinent who have increased adipocyte size [20], increased visceral adipose tissue [16–18], increased circulating free fatty acids [15], increased leptin levels [15,17], increased proinflammatory factors (e.g., increased C-reactive protein levels) [19], decreased anti-inflammatory factors (e.g., adiponectin) [15,17], increased insulin resistance [15] and increased CHD risk [21]. Anatomically, Asians have the typical findings of pathogenic adipose tissue, which includes an increase in the relative amount of visceral fat, and a lower number of adipocytes [20]. The reduced number of adipocytes may be due to a limited ability to undergo adipogenesis, which is a process that involves the recruitment and proliferation of more functional adipocytes [22]. If adipogenesis is impaired during positive caloric balance, then existing adipocytes must undergo hypertrophy to store excessive energy. If adipocyte hypertrophy results in metabolic dysfunction, then this may help account for the increase in metabolic disease in Asians compared with Caucasians at the same level of BMI [20]. This, again, supports the theory that within populations (and individuals) who are genetically predisposed, it is pathogenic adipose tissue that often ‘triggers’ the expression of metabolic disease. In fact, it is because the pathogenic potential of adipocyte and adipose tissue varies among those with differing genetic predispositions that international organizations have proposed that Asians should have different cut-off points for the determination of the terms ‘overweight’ and ‘obesity’ [23]. Acquired or environmental factors may also affect the pathogenic potential of adipose tissue. Hypercortisolemia, such as occurs with Cushing’s syndrome or exogenous corticosteroid use, is an example of a pathologic environment whose effects upon multiple body organs contribute to T2DM and other findings associated with the metabolic syndrome (increased waist circumference, hypertension and dyslipidemia). Glucocorticoids are normally anabolic in the liver, causing increased gluconeogenesis and increased glucose release. Hypercortisolism may also increase the appetite of patients, often resulting in positive caloric balance. Conversely, glucocorticoids are catabolic to muscle, causing muscle wasting and insulin resistance, and catabolic to adipose tissue, where lipolysis is modestly

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increased [1,24]. In peripheral, subcutaneous adipose tissue, exogenous corticosteroids may promote smaller adipocyte size, presumably due to catabolism and modest lipolytic activity [25]. However, visceral adipose tissue may undergo relative and absolute accumulation, due to a fourfold increase in glucocorticoid receptors in visceral adipose tissue when compared with peripheral, subcutaneous adipose tissue [26]. An increase in visceral adipocyte hypertrophy may be attributable to a glucocorticoid-induced increase in appetite and a glucocorticoid-induced increase in adipocyte differentiation and decrease in adipocyte proliferation – both of which promote adipocyte hypertrophy [27]. Additionally, the hyperinsulinemia that accompanies hypercortisol-induced insulin resistance may overwhelm the relatively minor lipolytic effects and promote an increase in triglyceride storage in visceral fat cells, a process termed lipogenesis. Overall, abdominal fat cells typically become enlarged and visceral adiposity is increased [25]. Finally, patients with hypercortisolism may have increased adipose tissue inflammatory responses, relative to those with less visceral adipose tissue accumulation [28]. Thus, hypercortisolemia is an example of an acquired environment that helps generate pathogenic adipose tissue. When coupled with a glucocorticoid-induced increase in gluconeogenesis from the liver and a glucocorticoid-induced increase in insulin resistance in the muscle, all of this contributes to the hyperglycemia so often found with hypercortisolemia. Adipogenesis

Typically, the cellular content of adipose tissue is approximately 50% adipocytes, with the remaining 50% being the stromal vasculature fraction of fibroblasts, endothelial cells, macrophages and preadipocytes. During positive caloric balance, increased storage of energy optimally occurs through the generation of added, functional fat cells, achieved through adipogenesis from preadipocytes [29,30]. Patients with lipodystrophy have a variable lack of adipose tissue that results in impaired adipose tissue function, manifested by low adiponectin levels and high circulating free fatty acids. Without adequate adipose tissue, storage of free fatty acids is inadequate and increased circulating free fatty acids often results in ‘lipotoxicity’ [31]. Lipotoxicity is characterized by ectopic fat deposition in muscle and liver (contributing to insulin resistance) and deposition in the pancreas (promoting insulinopenia), all potentially leading to T2DM [7,32]. Lipoatrophic mice have virtually no white adipose tissue and express a severe form of lipoatrophic T2DM. Surgical transplantation of functional adipose tissue in lipoatrophic mice reverses hyperglycemia, dramatically lowers insulin levels and improves muscle insulin sensitivity [33]. But just as too little adipose tissue can result in metabolic diseases [34], so can too much adipose tissue. This especially occurs when excessive body fat results in adipocyte hypertrophy, sometimes described as ‘acquired lipodystrophy’[35,36]. During positive caloric balance, adipocytes initially undergo

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hypertrophy, which normally triggers adipose tissue paracrine adipogenic signaling for the purpose of adding functional fat cells and towards maintaining adipose tissue physiologic functions during increased energy storage [37–39]. In the past, it has been suggested that the number of human adipocytes were fixed early in life and that a ‘fixed adipocyte-number’ predestined individuals to be lean or obese. However, this is no longer thought to be true [40]. Not only does adipocyte hypertrophy occur in humans [1,35,37,39,41–45], but the recruitment and proliferation of preadipocytes is also thought to occur in adult humans [1,35,39,41–43,46]. Adipogenesis is, therefore, an important physiologic process whose function or dysfunction may prevent or promote metabolic disease [1,47,48]. During persistent positive caloric balance, if adipogenesis is impaired after initial adipocyte hypertrophy, then further adipocyte hypertrophy may result in adipocyte dysfunction [47,49]. Some have even suggested that an increase in fat cell size might be viewed as a failure of adipocytes to adequately proliferate [35,50–52]. This may have pathological consequences. It has been known at least since the 1970s that during times of positive caloric balance, excessive fat cell enlargement results in adipocyte metabolic and immune abnormalities [53,54]. Animal studies have shown that a decrease in the expression of adipogenic genes is associated with metabolic diseases, such as T2DM [51]. Similarly, human studies have shown that in obese and T2DM patients, the proliferation and differentiation of adipocytes are decreased, as reflected by the decreased expression of adipogenic genes [42]. In summary, during times of positive caloric balance, if energy is stored predominantly through lipogenesis and fat cell hypertrophy of existing adipocytes, as opposed to adipogenesis with recruitment and differentiation of new fat cells and fat cell hyperplasia, then this may lead to pathologic adipose tissue responses that contribute to metabolic disease [1,14,35,36,42–45,49,51–60]. However, it is not the hypertrophy of individual fat cells alone that has potential adverse clinical consequences. Excessive expansion of the adipose tissue organ itself may also contribute to pathogenic processes. In order for adipose tissue growth to occur with maintenance of normal adipose tissue function, it must do so with an orderly and appropriate production of modulating and transcriptional factors [30,43,46,50,61], dissolution and reformation of the adipose tissue extracellular matrix [30,62], and angiogenesis [30,63]. Extracellular matrix (ECM) remodeling and angiogenesis are biological processes that are intimately linked [63], and disruption of either process may result in impaired adipose tissue function. For example, during positive caloric balance, an impairment of ECM formation limits adipose tissue growth, limits fat storage within adipose tissue and increases the potential for ectopic fat storage, which may contribute to metabolic diseases [31]. Furthermore, while adipogenesis may trigger ECM formation, adipocyte ECM factors may likewise affect adipogenesis [64]. If the appropriate and orderly formation of ECM is impaired, then this may also impair adipogenesis and thus contribute to adverse clinical consequences of pathogenic adipose tissue [35,52]. Similarly, an increase in adipose tissue

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growth also requires additional blood supply. If angiogenesis is impaired, then relative hypoxia may impair adipogenesis [65], which exacerbates adipocyte metabolic dysfunction, and may promote a net proinflammatory response [66–68], all contributing to metabolic disease. Thus, adipogenesis is a process that helps explain the seemingly paradoxical finding wherein not all overweight patients have metabolic disease and not all patients with metabolic disease are significantly overweight [1,2,5,69,70]. During positive caloric balance, the development of metabolic disease is more closely related to how the fat is stored (through adipocyte hypertrophy versus hyperplasia) than simply the amount of fat that is stored [1,44]. The determination as to whether adipocytes respond to positive caloric balance with hypertrophy versus hyperplasia is based upon genetic predisposition and the actions of multiple regulatory factors (BOX 1) [30]. Some adipocyte and nonadipocyte factors may have different effects within the adipogenic process, such as differing effects upon proliferation (creation of new adipocytes from preadipocytes) versus differentiation (increased maturity and lipogenesis within existing adipocytes). Angiotensin II impairs proliferation in humans (although reports are inconsistent in rodents [71]) and promotes differentiation [72–77]. Angiotensinogen impairs proliferation in humans (although reports inconsistent in rodents [71]) and promotes differentiation [72–75,77]. Autotaxin/lysophosphatidic acid promotes proliferation and impairs differentiation [78,79]. Catecholamines promote proliferation and impair differentiation [80]. Glucocorticoids impair proliferation and promote differentiation [27,81]. Finally, epidermal growth factor impairs proliferation and promotes differentiation [82]. This has practical, clinical implications in that glucocorticoids increase the differentiation of existing adipocytes (especially visceral adipocytes) relative to subcutaneous, peripheral adipocytes, while decreasing adipocyte proliferation. The resulting hypertrophy of visceral adipocytes, coupled with a decrease in the recruitment of functional subcutaneous, peripheral adipocytes, is a contributing cause of the T2DM, hypertension and dyslipidemia often found with hypercortisolemia [1,26,27]. Angiotensinogen/angiotensin II may unfavorably decrease adipogenesis. Conversely, enhanced adipogenesis is one of the proposed reasons why angiotensin-converting enzyme (ACE) inhibitors and angiotensin II blockers may improve metabolic disease, including T2DM [72]. Additionally, ACE inhibitors and angiotensin II receptor blockers (ARBs) increase peroxisome proliferator-activated receptor (PPAR)-γ activity (which promotes adipogenesis), and have other effects that may involve adipose tissue. ACE inhibitors and ARBs may also increase adiponectin levels, increase translocation of glucose transporters, upregulate tyrosine phosphorylation of insulin receptor substrate-1 and enhance bradykinin and nitric oxide activities [7,73,83–88]. Finally, weight gain is often associated with an increase in catecholamine activity, as may be mediated through increased circulatory and CNS leptin levels [89]. An increase in catecholamines would be

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Box 1. Examples of factors influencing adipogenesis. Modulating and transcriptional factors produced by adipocytes • Adipocyte determination and differentiation factor-1/ sterol regulatory element-binding proteins • CCAAT/ enhancer-binding proteins • Peroxisome proliferator-activated γ receptors • E2F proteins • Cyclin D • Cyclin-dependent kinases • Nuclear receptors, such as farnesoid X receptor, liver X receptor and retinoid X receptors

Extracellular matrix factors produced by adipocytes • Actin • Bone morphogenic protein • Collagen-binding protein (colligin) • Collagens • Cystatin C • Cysteine protease cathepsin S (CTSS) • Fibroblast growth factor • Fibronectin • Gelsolin • Integrin • Laminin • Matrix metalloproteases • Myosin • Nidogen (entactin) • Osteonectin (secreted protein acidic and rich in cysteine [SPARC]) • Procollagen • Stromal cell-derived factor 1 • Tubulin • Vimentin

Angiogenesis factors produced by adipocytes • Adiponectin • Angiogenin • Angiopoietin-2 • Autotaxin • Endostatin • Fibroblast growth factor • Hepatocyte growth factor • Hypoxia inducible factor-1 • Leptin • Monobutyrin • Matrix metalloproteinases • Nitric oxide synthase

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Box 1. Examples of factors influencing adipogenesis (cont.).

• Osteonectin (SPARC)

Adipose tissue factors that inhibit adipogenesis

• Pigment epithelium-derived factor

• Androgens (testosterone)

• Plasminogen activator inhibitor-1

• Angiotensin II (inhibits preadipocyte recruitment)

• Platelet derived growth factor • Prostaglandin E2

• Angiotensin-converting enzyme (inhibits preadipocyte recruitment)

• Prostaglandin I2 (prostacyclin)

• Angiotensionogen (inhibits preadipocyte recruitment)

• Tissue factor

• Autotaxin (inhibits differentiation)

• Transforming growth factor

• Ceramide

• Vascular endothelial growth factor

• Chemerin

Other adipose tissue factors that may facilitate adipogenesis • Acylation-stimulating protein (mainly lipogenesis) • Adipogenin • Adiponectin • Agouti protein • Angiotensin II (promotes differentiation) • Angiotensinogen (promotes differentiation) • Angiotensin-converting enzyme (promotes differentiation) • Autotaxin (promotes proliferation) • cAMP-response element-binding protein

• Epidermal growth factor (inhibits proliferation) • Insulin-like growth factor-binding protein • IL-1, IL-6, IL-8, IL-11 • Leptin (inconsistent reports in medical literature) • Leukemia inhibitory factor (inconsistent reports in medical literature) • Lysophosphatidic acid (inhibits differentiation) • Macrophage inflammatory protein-1α • Mitogen-activated protein kinase • Monocyte chemoattractant protein-1 • Necdin

• Epidermal growth factor (promotes differentiation)

• Plasminogen activator inhibitor (inconsistent reports in medical literature)

• Estrogens

• Pre-adipocyte factor-1

• F-Box proteins (such as S-phase kinase-associated protein [Skp]2)

• Prostaglandin F2

• Free fatty acids • Galectin 12 (promotes differentiation) • Hormone sensitive lipase • Insulin-like growth factor

• Resistin (inconsistent reports in medical literature) • Resistin-like molecules • Retinoids (inconsistent reports in medical literature) • Transforming growth factor-β • TNF-α

• Leptin (inconsistent reports in medical literature) • Leukemia inhibitory factor (inconsistent reports in medical literature)

Other factors, not necessarily adipocyte in origin, that facilitate adipogenesis

• Lipin

• Catecholamines (neurologic signaling promotes adipocyte hyperplasia)

• Lysophosphosphatidic acid (promotes differentiation)

• Prolactin

• Hormones – Estrogens – Ghrelin (inconsistent reports in the literature) – Glucocorticoids (stimulates differentiation) – Insulin – Insulin growth factor-1 – Prolactin – Thyroid hormone

• Resistin (inconsistent reports in medical literature)

• Lipoproteins (very-low-density lipoproteins)

• Macrophage colony stimulating factor • Neuronatin • Nitric oxide • Phosphoinositide 3-kinase • Plasminogen activator inhibitor-1 (inconsistent reports in medical literature)

• Retinoids (inconsistent reports in medical literature)

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Box 1. Examples of factors influencing adipogenesis (cont.). • Lipids – Endocannabinoids (anandamide) – Dietary fats – Free fatty acids – Prostaglandins (PGE2, PGI2, PGJ2) • Proteins – Plasminogen/plasmin – Neuropeptide Y – Protein kinase C (PKC-βI) – Protein kinase C inhibitor

Other factors, not necessarily adipocyte in origin, that impair adipogenesis • Androgens • Catecholamines (neurologic signaling decreases adipocyte hypertrophy) • Cytokines (such as TNF-α) • Flavonoids • Ghrelin (inconsistent reports in the literature) • Glucagon-like peptide-1 • Glucocorticoids (impairs proliferation) • Growth factors – Epidermal growth factor, (which impairs proliferation and promotes differentiation) – Fibroblast growth factor – Platelet-derived growth factor – Transforming growth factor-β – Tumor growth factor β • Interferon • Interleukins • Protein kinase C (PKC-delta) • Prostaglandins (PGF2)

expected to increase adipocyte proliferation and lipolysis, and thus potentially attenuate progression to metabolic disease. However, a leptin-mediated increase in catecholamines levels may also increase blood pressure. With this exception aside, the favorable influence of catecholamines on lipolysis and adipogenesis helps explain why impairment of these favorable metabolic activities, such as might occur through the dysfunction of the sympathetic nervous system, may contribute to obesity and T2DM [90]. Fat storage

The pathogenesis of metabolic diseases is significantly influenced by not only how the fat is stored (hypertrophy versus hyperplasia), but also where the fat is stored [91]. Patient populations described as metabolically healthy (no metabolic disease), but obese, often have less visceral adipose tissue distribution than obese patients with metabolic disease [92,93]. Conversely, patients who are metabolically obese (those with metabolic disease), but normal weight,

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often have more visceral adipose tissue than individuals of similar weight and no metabolic disease [92]. Such clinical findings are explained by the different intrinsic activities of fat depots [74,94–100]. Visceral adipose tissue accumulation is the fat depot most characterized as being associated with an increased risk of metabolic disease [97,99,101–109]. This is whether the visceral adipose tissue accumulation occurs by hypertrophy or hyperplasia [1,97,101–108,110,111]. Conversely, if subcutaneous, peripheral adipose tissue undergoes hyperplasia with a generation of smaller and more functional adipocytes, then this added functionality may attenuate or reduce the risk of metabolic disease [1,35,36,43,51,52,56,58,112]. Location is one of the more important reasons why different fat depots have different pathogenic potential. Visceral adipose tissue, which represents approximately 20% of total body fat, secretes various adipocyte factors (such as free fatty acids) into the portal vein, which supplies 80% of the hepatic blood supply (TABLE 1) [107]. Also, visceral adipose tissue is genetically predetermined [113] to have different functions than subcutaneous, peripheral adipose tissue (which represents approximately 80% of total body fat). For example, these two fat depots differ in the production of bioactive molecules, the activity of various receptors and the enzymatic processes involved with fat metabolism (TABLE 1) [47,114–116]. An important clinical implications of these differences is that when corrected for the same age, men are at higher CHD risk than women. Comparatively, men often store more fat in the visceral region, representing a so called ‘android’ adipose tissue distribution [117,118]. An increase in visceral adiposity promotes metabolic diseases that are important CVD and CHD risk factors (T2DM, hypertension and dyslipidemia). Conversely, women often have increased adipose tissue accumulation and increased adipocyte size within the peripheral, subcutaneous region, representing a so called ‘gynoid’ adipose tissue distribution [119–122]. These gender differences in adipose tissue distribution, described since the 1940s [123], can be at least partially explained by the influences of sex hormones [1,47,74] . Analogous to the effects glucocorticoids may have on visceral adipose tissue distribution [1,26,74,124], sex hormones can also affect adipose tissue distribution. Androgens are associated with increased visceral adipose tissue distribution, while estrogens are associated with increased peripheral, subcutaneous adipose tissue distribution [1,26,74,125,126]. Adipose tissue depots not only differ in their metabolic activity, but also in the degree of their metabolic activity. Visceral adipose tissue, such as intraperitoneal (omental, mesenteric and umbilical), extraperitoneal (peripancreatic and perirenal), and intrapelvic (gonadal/epidydimal and urogenital) adipose tissue have a higher degree of metabolic activity compared with subcutaneous, peripheral adipose tissue (truncal, gluteofemoral, mammary and inguinal) [47,101,127]. Some have suggested that subcutaneous adipose tissue in the abdominal region has metabolic activity, such as lipolysis and the release of inflammatory factors, between that of visceral and subcutaneous, peripheral adipose tissue [101,111,128–130]. Accordingly, subcutaneous, abdominal adipose tissue may contribute to worsening of CHD risk factors [131].

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Table 1. Comparison of subcutaneous, peripheral adipose tissue versus visceral adipose tissue*. Characteristic

Function

General characteristics Fat amount relative to total body fat

Subcutaneous > visceral

Metabolic activity

Subcutaneous < visceral

Greater differentiation of preadipocytes

Subcutaneous > visceral

Apoptosis

Subcutaneous < visceral

Lipolysis/lipogenesis Inhibition of intra-adipocyte lipolysis by insulin

Subcutaneous > visceral

Inhibition of intra-adipocyte lipolysis by prostaglandins

Subcutaneous > visceral

Inhibition of intra-adipocyte lipolysis by adenosine

Subcutaneous > visceral

Storage of circulating postprandial FFAs

Subcutaneous > visceral

Stimulation of intra-adipocyte lypolysis by catecholamines

Subcutaneous < visceral

Direct access to the liver by portal vein

Subcutaneous < visceral

Increased net release of FFAs into portal vein

Subcutaneous < visceral

Increased portal vein delivery of FFAs and glycerol, increasing hepatic triglyceride and glucose production, thus promoting dyslipidemia and hyperglycemia

Subcutaneous < visceral

Adipocyte receptors Lypolytic β-adrenergic receptors

Subcutaneous < visceral

Antilipolytic α 2-adrenergic receptors

Subcutaneous > visceral

Glucocorticoid receptors

Subcutaneous < visceral

Androgen receptors

Subcutaneous < visceral

Estrogen receptors

Subcutaneous > visceral‡

Peroxisome proliferators-activated receptor γ

Adipocyte factors

Subcutaneous < visceral

Leptin

Subcutaneous > visceral

Adiponectin

Subcutaneous < visceral

IL-6

Subcutaneous < visceral

Plasmininogen activator inhibitor-1

Subcutaneous < visceral

Angiotensinogen

Subcutaneous < visceral

Cholesteryl ester transfer protein

Subcutaneous > visceral

Acylation stimulating protein

Subcutaneous < visceral

TNF-α

Subcutaneous < visceral

Hormone sensitive lipase

Subcutaneous > visceral

Lipoprotein lipase

Subcutaneous < visceral

Other fat depots (such as abdominal subcutaneous, intraorgan and periorgan fat) may have metabolic activity between that of peripheral subcutaneous fat and visceral fat, have function similar to that of peripheral subcutaneous fat or visceral fat, or have fat function that has not been well-defined. ‡ While adipose tissue may contain estrogen receptors, the increase in the subcutaneous, peripheral adipose tissue distribution often found in many women may be more related to estrogen-induced upregulation of the antilipolytic a 2α-adrenergic receptors found in peripheral subcutaneous fat and not visceral fat. § Specific adipoctye factors reflect either increased production or increased gene expression, and the relationships to fat depots are not always consistent in the medical literature. The production and gene expression of adipocyte factors may be influenced by increased fat accumulation. FFA: Free fatty acid. Reproduced with permission from [47].

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Table 1. Comparison of subcutaneous, peripheral adipose tissue versus visceral adipose tissue* (cont.). Characteristic

Function

Retinol binding protein

Subcutaneous = visceral

Insulin-like growth factor-1

Subcutaneous = visceral

Insulin-like growth factor-1 binding protein

Subcutaneous = visceral

Monobutyrin

Subcutaneous = visceral

Uncoupling proteins-1

Subcutaneous > visceral

Uncoupling proteins-2

Subcutaneous > visceral

*Other fat depots (such as abdominal subcutaneous, intraorgan and periorgan fat) may have metabolic activity between that of peripheral subcutaneous fat and visceral fat, have function similar to that of peripheral subcutaneous fat or visceral fat, or have fat function that has not been well-defined. ‡ While adipose tissue may contain estrogen receptors, the increase in the subcutaneous, peripheral adipose tissue distribution often found in many women may be more related to estrogen-induced upregulation of the antilipolytic a 2α-adrenergic receptors found in peripheral subcutaneous fat and not visceral fat. § Specific adipoctye factors reflect either increased production or increased gene expression, and the relationships to fat depots are not always consistent in the medical literature. The production and gene expression of adipocyte factors may be influenced by increased fat accumulation. FFA: Free fatty acid. Reproduced with permission from [47].

Similarly, periorgan adipose tissue (pericardial, perimuscular, perivascular, orbital and paraosseal) may also have pathogenic potential through metabolic activities including lipolysis and the release of inflammatory factors, with an intrinsic activity between that of visceral adipose tissue and subcutaneous, peripheral adipose tissue [47,128,133]. Pericardial and perivascular adipose tissue accumulation may directly promote CHD and peripheral vascular disease [133–137]. It has traditionally been assumed that atherosclerosis is exclusively the result of pathologic interactions of intralumenal processes within arterial subendothelia. However, pathogenic pericardial and perivascular adipose tissue may directly contribute to atherosclerosis through an ‘outside to inside’ (from the outside of the vessel to the endothelium) vascular atherogenic model [1,133–135]. Although subcutaneous adipose tissue is sometimes thought of as ‘protective’, even excessive subcutaneous adipose tissue may become pathogenic [138,139]. If during positive caloric balance, the recruitment and proliferation of smaller and more functional subcutaneous adipocytes occurs, then the risk of developing metabolic disease may be decreased. This may be characterized as ‘protective’ through providing additional adipose tissue functionality, including improved energy (free fatty acid) storage capacity. However, if adipogenesis is impaired and subcutaneous adipocytes become sufficiently enlarged to become dysfunctional and pathogenic, then this may contribute to metabolic diseases, such as T2DM [14]. One of the more notable ways in which subcutaneous adipose tissue may be pathogenic involves the production of leptin (TABLE 1). In obesity due to leptin deficiency, administration of leptin dramatically reduces body fat, and corrects almost all of the associated metabolic abnormalities [140]. However, in humans without leptin deficiency, leptin functions mainly to signal energy adequacy, and is best viewed as a hormone whose reduced levels (such as through negative caloric balance) promote increased feeding and decreased energy expenditure [1,47,141]. In the absence of leptin deficiency, the weight loss effects of

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increasing leptin levels appears to be near maximal at physiologic levels [142]. This may be, at least in part, because the secretion of leptin by enlarging adipocytes may be simultaneously accompanied by adipose tissue physiological responses that block leptin activity (a proposed form of ‘leptin resistance’) [143]. Nonetheless, while further increases in leptin levels may potentially reduce abnormalities of glucose and lipid metabolism [1], hyperleptinemia may increase blood pressure [1,89,144–149]. Subcutaneous adipose tissue is the major source of circulating leptin because subcutaneous adipose tissue is quantitatively the largest fat depot; subcutaneous adipocytes are larger than visceral or omental adipocytes; and leptin gene expression may be increased within this fat depot [150]. Biopsy studies of femoral subcutaneous adipose tissue have shown that hyperleptinemia is more closely associated with adipose cell hypertrophy than with adipose tissue hyperplasia [151]. Thus, to the extent that hyperleptinemia contributes to hypertension and to the degree that hyperleptinemia is more related to hypertrophied subcutaneous adipose tissue than visceral adipose tissue, then hypertrophy of subcutaneous adipocytes may lead to hyperleptinemia-induced hypertension. This would be supported by the findings that hypertension is directly and continuously related to BMI, [5] and that arterial compliance decreases and blood pressure increases in overweight and obese individuals compared with normal weight individuals, even when their hip circumference and sum of skin folds (measures of subcutaneous adipose tissue) are increased [152]. However, when adjusted for body surface area, hip circumference and sum of skin folds may be inversely related to arterial compliance, even while waist circumference may or may not have a significant correlation. This suggests that while both subcutaneous and visceral adipose tissue may contribute to hypertension, particularly when accompanied by adipocyte hypertrophy, a relative increase in visceral adipose tissue often has a greater blood pressure-raising effect. This may possibly be due to the deleterious effects of visceral adipose tissue upon various adipocyte factors

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(TABLE 1), such as IL-6, C-reactive protein and TNF-α, directly leading to endothelial dysfunction [152]. Obesity-induced insulin resistance may also impair the release of otherwise vasodilatory, endothelia nitric oxide, which is another mechanism that might increase blood pressure [152]. Finally, while visceral adipose tissue is the major contributor to portal free fatty acids, subcutaneous adipose tissue accounts for the majority of systemic circulating free fatty acids. Specifically, the majority of postabsorptive systemic free fatty acids, which may most adversely affect muscle, pancreas and vasculature [153], are derived from upper body subcutaneous adipose tissue, with only approximately 15% being derived from visceral adipose tissue [153,154]. Thus, while mostly described with central adiposity, the lipolytic activity of both visceral and subcutaneous adipose tissue have the potential to be pathogenic. It has also been proposed that the pathogenic effects of visceral adipose tissue may contribute to the pathogenic responses of both abdominal and gluteal subcutaneous adipose tissue. Insulin inhibits lipolysis through trapping circulating free fatty acid within adipocytes [1]. Impaired insulin activity from visceral adipose tissue-induced insulin resistance [154] might increase adipocyte lipolysis, increase circulating free fatty acids, and further worsen insulin resistance. Thus, an increase in visceral adiposity may cause or exacerbate the pathogenic potential of subcutaneous adipose tissue. Recognizing their physiologic and potential pathologic importance, various fat depots are frequently measured in clinical trials and sometimes assessed clinically [155]. From a research standpoint, while ultrasound is sometimes used for evaluation of intra-abdominal adipose tissue, computed tomography (CT) and magnetic resonance imaging (MRI) are the imaging procedures most widely used to assess visceral fat depots [156], with CT often considered to be the gold-standard imaging technique for assessing various fat depots [132,136,157–159]. MRI may also provide good imaging for visceral adipose tissue and intramuscular fat, but perhaps less so for subcutaneous or intermuscular adipose tissue [132,160]. From a clinician standpoint, measurement of height, weight and waist circumference may be diagnostically helpful. An increase in abdominal girth may be more specifically associated with an increased amount of visceral fat and, thus, more predictive of an increased risk of metabolic disease when compared with BMI alone [18,106,166–163]. Alternatively, since an increase in BMI is generally associated with an increased risk of metabolic disease [5,6], some have suggested that BMI performs at least as well as waist circumference in identifying the potential for insulin sensitivity abnormalities and CHD risk factors [162].

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are derived from the lipolysis of stored triglycerides, and regulated by adipocyte and nonadipocyte factors (BOX 2). If intracellular adipocyte hydrolysis of triglycerides (lipolysis) exceeds intracellular adipocyte esterification of free fatty acids (lipogenesis), then free fatty acids undergo a net release into the circulation. A sustained, excessive net increase in circulating free fatty acids contributes to metabolic disease [31]. Chronic increases in circulating free fatty acids worsen glucose metabolism due to ‘lipotoxic’ effects upon muscle and liver (contributing to insulin resistance) [153] and pancreas (contributing to insulinopenia) [31,97,164,165]. This is an important reason why David Savage suggests [166]: ‘The last decade has seen a shift from the traditional ‘glucocentric’ view of diabetes to an increasingly acknowledged ‘lipocentric’ viewpoint.’ Increases in circulating free fatty acids are also an independent risk factor for hypertension, possibly due to free fatty acid-induced insulin resistance, which itself contributes to high blood pressure [167,168]; impairment of endotheliumdependent vasodilation [167,168]; and other microvascular dysfunctions leading to hypertension [167,168]. Finally, increases in circulating free fatty acids contribute to the typical dyslipidemia found with the ‘metabolic syndrome,’ which includes hypertriglyceridemia, reduced high-density lipoprotein-cholesterol levels, and abnormalities of lipoprotein particle size and subclass distribution, such as an increased proportion of small, dense low-density lipoprotein particles [1,169, 170]. Adipocyte factors

While its function has sometimes been characterized as little more than storing energy, adipose tissue is clearly an active endocrine organ (BOX 3) [48,74,171–173]. Adipocytes and adipose tissue are actively involved in metabolic processes such as angiogenesis, adipogenesis, ECM dissolution and reformation, lipogenesis, growth factor production, glucose metabolism, production of factors associated with the renin–angiotensin system, lipid metabolism, enzyme production, hormone production, steroid metabolism, immune response, hemostasis and element binding (BOX 3). The disruption of these adipose tissue processes, as occurs with adipocyte hypertrophy and visceral adipose tissue accumulation, results in adipocyte factor abnormalities that are not only associated with, but may be important contributors to metabolic diseases (TABLE 2) [1,47,169]. Inflammation

Free fatty acid metabolism

Adipose tissue is the major energy storage organ of the body. Approximately 80% of adipose tissue weight is lipid, and over 90% of lipids are stored triglycerides [155]. The major secretory product from adipose tissue is free fatty acids [29], which

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Adipose tissue is not only an active endocrine organ, but it is also an active immune organ [174–180]. An increase in body fat is directly related to the number of macrophages found in adipose tissue [178,179,181,182]. A net proinflammatory response of adipose tissue may result from: adipose tissue secretion of proinflammatory factors; adipose tissue secretion of factors

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Box 2. Examples of adipose tissue factors that affect free fatty acid metabolism. • Acetyl-coenzyme A carboxylase • Acetyl-coenzyme A synthetase • Acylation-stimulating protein • Adenosine • Adenosine monophosphate protein kinase (AMPK) • Adiponutrin • Adipophilin (adipose differentiation-related protein) • Adipsin (complement factor D) • Adrenomedullin • Agouti protein • Androgens • Angiotensin I and II • Angiotensinogen • Annexin • Apolipoprotein C1 • Aquaporin 7 • Carnitine palmitoyl transferase-1 • Caveolin • Desnutrin (adipocyte triglyceride lipase [ATGL]) • Estrogens • Fasting-induced adipocyte factor • Fatty acid-binding protein • Fatty acid synthase • Fatty acid translocase (CD36) • Fatty acid transport protein • Hormone sensitive lipase • Interleukins • Leptin • Lipin • Lipoprotein lipase

and significant amounts of other inflammatory factors, including interleukins, cathepsin S, macrophage-inhibitory factor, nerve growth factor and inducible nitric oxide synthase (iNOS) [178,181,188,189]. Furthermore, the origin of increases in inflammatory factors found in patients with excessive body weight are often derived from nonadipose tissue [172,190], with pathogenic adipose tissue promoting the inflammatory responses from other body organs. An example would be hepatic C-reactive protein production in response to adipocyte/adipose tissue IL-6 release, as may occur with obesity [191]. As previously described, adipocytes are metabolically active and have the capacity to secrete nonproteins factors such as prostaglandins, fatty acids, monobutyrin, and steroid hormones. From an immune standpoint, adipocytes and adipose tissue also produce bioactive proteins, termed adipokines, which are secretory factors that include classic cytokines, complement factors, enzymes, growth factors, hormones and matrix proteins. Increased secretion of proinflammatory adipokines with cytokine activity may contribute to metabolic disease, including atherosclerosis [1,47,180,192]. Adipose tissue-derived inflammatory factors that are potentially pathogenic include acute phase reactants, such as plasminogen activator inhibitor-1 [193] and possibly C-reactive protein [194,195], proteins of the alternative complement system [1,47,172], chemotactic/chemoattractant adipokines [1,47], eicosanoids/prostaglandins [1,47], and reduced secretion of anti-inflammatory factors (BOX 4) [1,47,192]. It is not known which, if any, proinflammatory factors are best to measure in relation to adipose tissue’s promotion of metabolic disease. Among the more commonly described adipose tissue inflammatory factors associated with T2DM are TNF-α, IL-6 [196] and C-reactive protein, which are all positively correlated to adipocyte size [197]. Adiponectin is the adipocyte/adipose tissue antiinflammatory factor whose decreased levels are best described to be associated with metabolic disease. Adiponectin levels are negatively correlated with adipocyte size [197].

• Perilipin • Phosphoenolpyruvate carboxykinase (PEPCK) • Prostaglandins • S3-12 • Stearoyl-CoA desaturase • Tail interacting protein 47 • Transcription factors • TNF-α

that stimulate other tissues to produce inflammatory factors; and decreased production of anti-inflammatory factors [1,29]. The net proinflammatory response associated with pathogenic adipose tissue is an important contributor to metabolic disease [1,166,180,183–187]. Adipose tissue inflammatory factors are produced by both adipocytes and associated inflammatory cells, such as adipose tissue-related macrophages. Adipose tissue macrophages may be responsible for almost all adipose tissue TNF-α expression

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Cross-talk & interactions with other body tissues

The onset or worsening of many metabolic diseases might best be considered the net result of a pathologic partnership between adipose tissue and limitations and/or dysfunction of other body organs. Impaired cross-talk with adjacent adipocytes, such as paracrine signaling [198], may account for impaired adipogenesis and promotion of metabolic disease [199]. Crosstalk is defined as biological signaling exchanges between body organs. This cross-talk is important for the integration of metabolic functions of adipocytes/adipose tissue with other adipocytes, other adipose tissue depots and other body organs. Disrupted or adverse cross-talk between adipose tissue and other body organs may contribute to metabolic disease [200,201]. Organs systems affected by signaling from adipose tissue include the nervous system [202], immune system [176], skeletal muscle [203–206], cardiovascular system [133,167,187,207–213] liver [214,215], gastrointestinal system [216], adrenal cortex [217]

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Box 3. Examples of adipose tissue properties that highlight its activity as a metabolic organ.

Box 3. Examples of adipose tissue properties that highlight its activity as a metabolic organ (cont.).

Receptors for traditional peptide and glycoprotein hormones

Catecholamine receptors

• Adiponectin

• Muscarinic receptors

• Angiotensin II type 1 and 2

• Nicotinic receptors

• Catecholamines such as α1 and α2; β1, β2, β3

• Gastrin/cholecystokinin • Glucagon

Other receptors

• Glucagon-like peptide-1

• Adenosine

• Growth hormone

• Cannabinoids

• Insulin • Insulin-like growth factors

• Lipoproteins (high-density lipoprotein, low-density lipoprotein, very-low-density lipoprotein)

• Thyroid stimulating hormone

• Melanocortins • Neuropeptide Y

Receptors for nuclear hormones

• Prostaglandins

• Androgens • Estrogens • Glucocorticoids • Nuclear factor-kB • Progesterone • Thyroid hormone • Vitamin D

Other nuclear receptors • Peroxisome proliferator-activated receptor (PPAR) α receptors • PPAR β receptors • PPAR δ receptors • PPAR γ receptors • Farnesoid X receptors • Liver X receptors • Retinoid X receptors

Receptors for cytokines or adipokines with cytokine-like activity • Adiponectin • Interleukins • Leptin • Transforming growth factor-β • TNF-α

Receptors for growth factors • Epidermal growth factor • Fibroblast growth factor • Hepatocyte growth factor • Insulin-like growth factor • Platelet-derived growth factor • Transforming growth factor-β • Tumor growth factor • Vascular endothelial growth factor

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and thyroid [218]. The best example might be the CNS [202,219–226], which would include the CNS activity of leptin/insulin [143,224,227–235], pro-opiomelanocortin (POMC)/cocaine amphetamine-regulated transcript (CART) [223,229,236,237], neuropeptide Y (NPY)/agouti-related peptide (AgRP) [223,229,238–242], melanocortin system, [223,236,239,243–248] and CNS neuroendocrine activity (e.g., thyroid-releasing hormone and corticotropin-releasing hormone) [223,249,250]. More recently, the endocannabinoid system is becoming more recognized as playing an important role in adipocyte function, and the pathogenic potential of adipose tissue [7,223,251–259]. Abnormalities of other organ systems may also affect the pathogenic potential of adipose tissue [260–262]. In addition to impaired cross-talk signaling, nonadipose body organs may have inherent or acquired dysfunction or limitations that increase the risk of developing metabolic disease. Some patients may have an inability to metabolize intramuscular fat due to genetic or acquired ‘inflexibility’ in their oxidation of free fatty acids [263]. If fat cell hypertrophy and/or increase in visceral adipose tissue results in increased circulating free fatty acids, this may cause excessive ectopic free fatty acid storage in muscle. Such ‘lipotoxicity’ is pathogenic in that the accumulation of intramyocellular lipids, such as diacylglycerol, fatty acyl CoA and ceramides, promote insulin resistance [263–267]. Fat weight loss through hypocaloric nutritional intervention may not necessarily improve ‘inflexible’ muscle’s inherent ability to metabolize free fatty acids. But such intervention is nonetheless therapeutic in that through fat weight loss, the triglyceride content of skeletal muscle is reduced, improving insulin sensitivity [266]. Thus, in the presence of limitations or dysfunction of target organs, positive caloric balance may promote metabolic disease, while negative caloric balance may improve metabolic disease. Conversely, if skeletal muscle were to become ‘hyperflexible’ (i.e., develop an increased capacity to metabolize free fatty acids), either through genetic predisposition or through the use of drug therapies (such as PPAR-γ agents), then metabolic disease may be theoretically prevented or improved [268], even in the presence of pathogenic adipose tissue.

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Table 2. Abnormalities in adipose tissue factors that may contribute to metabolic disease*. Type 2 diabetes mellitus

Hypertension‡

Dyslipidemia

3 β hydroxysteroid dehydrogenase 11 β-hydroxysteroid dehydrogenase type 1 Acetyl-coenzyme A carboxylase Acylation-stimulating protein Adenosine Adiponectin Adiponutrin Adipophilin differentiation-related protein Adipsin (complement factor D) Adrenomedullin Agouti protein Angiotensin I & II Angiotensin-converting enzyme Angiotensinogen Apelin Apolipoproteins C1, D and/or E Aquaporin 7 Autotaxin (lysophospholipase D) Cathepsin D and G Caveolin-1 Ceramide Cholesterol ester transfer protein Chymase Clathrin Complement factors C3 and/or B C-reactive protein Desnutrin Dynamin Ectonucleotide pyrophosphatase/ phosphodiesterase-1 Endothelin Flotillin-1 Free fatty acids and factors associated with free fatty acid metabolism (BOX 2) Glucose transporter 4 *The list of adipose tissue factors in this table is not exhaustive, as the number of adipocyte factors potentially contributing to metabolic disease is undergoing constant update. Similarly, more research regarding the adipoctye factors in this table will probably reveal that they have additional effects upon the metabolic diseases listed. ‡ Hypertension may also be increased due to fat mass effects, such as compression of kidneys, obesity-induced sleep apnea, direct effects upon the heart and increased sympathetic nervous system activity.

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Table 2. Abnormalities in adipose tissue factors that may contribute to metabolic disease* (cont.). Type 2 diabetes mellitus

Hypertension‡

Dyslipidemia

Glutamine Glycerol Hormone sensitive lipase Hypoxia inducible factor-1 Insulin-like growth factor-binding protein IGF-1 IL-6 IL-10 IL-11 Leptin Lipin Lipoprotein lipase Lysophospholipids Monocyte chemoattractant protein-1 Neuronatin Nitric oxide synthase Omentin Perilipin Phosphoenolpyruvate carboxykinase Phosphoinositide 3-kinase Phospholipids transfer protein Plasminogen activator inhibitor-1 Prostaglandins Protein kinases (mitogen-activated protein kinase, protein kinase B, protein kinase) Renin Resistin Retinol-binding protein S3-12 Sex hormones Stearoyl-CoA desaturase Tail interacting protein 47 Tonin TNF-α Visceral adipose tissue-derived serpin Visfatin *The list of adipose tissue factors in this table is not exhaustive, as the number of adipocyte factors potentially contributing to metabolic disease is undergoing constant update. Similarly, more research regarding the adipoctye factors in this table will probably reveal that they have additional effects upon the metabolic diseases listed. ‡ Hypertension may also be increased due to fat mass effects, such as compression of kidneys, obesity-induced sleep apnea, direct effects upon the heart and increased sympathetic nervous system activity.

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The liver is also an important organ in oxidizing and metabolizing free fatty acids. With positive caloric balance, adipocyte hypertrophy and visceral adipose tissue accumulation may increase the flow of free fatty acids to the liver, increasing hepatic lipid content, and resulting in the common clinical finding of hepatosteatosis (‘fatty liver’). Patients with ‘inflexibility’ in hepatic free fatty acid oxidization may be more susceptible to lipid accumulation in the liver and, thus, more prone to developing insulin resistance and dyslipidemia [34]. Finally, in patients with an inherent or acquired insulinopenia, the chronic increase in circulating free fatty acid from pathogenic adipose tissue and ectopic free fatty acid deposition in the pancreas may decrease insulin secretion and also contribute to T2DM [269]. In summary, adipose tissue does not act alone in its potential to promote metabolic disease. In patients who are predisposed to metabolic disease due to genetic background, age [270], gender, nutritional intake, physical activity level, comorbid conditions, concurrent drug treatments and other predispositions, it is the limitation or dysfunction of other body organs that determines the degree by which the pathogenic potential of adipose tissue will promote metabolic disease. Thus, the variability in fat weight gain which results in metabolic disease is not only due to how fat is stored (adipogenesis), where the fat is stored (visceral versus other fat depots), but is also dependent upon the signaling and interactions with other body organs.

Box 4. Inflammatory factors associated with adipose tissue*. Adipokines with cytokine activity • Adipsin • IL-1B, IL-6, IL-8, IL-17D, IL-18 • Leptin • Macrophage colony-stimulating factor • Macrophage-inhibitor factor • Monocyte chemotactic protein-1 • Regulated on activation, normal T-cell expressed and secreted (RANTES) • Resistin • TNF-α • Visceral adipose tissue-derived serpin

Acute phase reactants • α-1 acid glycoprotein • Amyloid A • Ceruloplasmin • C-reactive protein • Haptoglobin • IL-1 receptor antagonist • Lipocalins • Metallothionein • Pentraxin-3

Adverse clinical consequences of excessive fat mass

Excessive fat mass alone may contribute to other clinical disorders, such as cardiovascular [138,139,207,271–273], neurologic [138,139], pulmonary [138,139,271], musculoskeletal [138,139], dermatologic [138,139], gastrointestinal, [138,139] genitourinary [138,139], renal [138,139,272] and psychological diseases [138,139].

• Plasminogen activator inhibitor-1

Adipokines of the alternative complement system • Adipsin • Acylation-stimulating protein • Complements C3 and B

Chemotactic/chemoattractant adipokines

Expert commentary: defining pathogenic adipose tissue & its metabolic complications

• Eotaxin

Currently, the most common term defining the clustering of metabolic abnormalities that increase atherogenic risk is the ‘metabolic syndrome.’ The diagnostic parameters for metabolic syndrome include increased waist circumference, elevated fasting glucose levels, elevated blood pressure, elevated triglyceride levels and low HDL-C levels [169,272–277]. However, this term does not reflect a description of the unified, pathophysiologic process leading to these clustering of metabolic disorders. Nor is there uniform agreement as to its definition [274,169]. Finally, the diagnosis of the metabolic syndrome may not be a better predictor of future metabolic disease than assessment of its individual components [278–280]. Many (but not all) clinicians find the term metabolic syndrome useful, [281–276,284–286] with the hope that corralling key physical examination and laboratory measures into a group may help better focus attention to parameters that increase CHD risk. However, from a patient

• Monocyte chemoattractant protein-1

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• Interferon inducible protein • Macrophage colony-stimulating factor • Macrophage migration inhibitory factor • Stromal derived factor-1 • RANTES • Resistin • TNF-α • Vascular adhesion protein-1 • Vascular cell adhesion molecule-1

Eicosanoids/prostaglandins • Prostaglandin E2 *A net proinflammatory response that may contribute to metabolic disease occurs with increased secretion of adipose tissue proinflammatory factors, and a decrease in secretion of anti-inflammatory adipose tissue factors.

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Box 4. Inflammatory factors associated with adipose tissue* (cont.). Anti-inflammatory adipose tissue factors • Adiponectin • Annexin-1 • IL-10 • IL-6 • Nitric oxide. • Transforming growth factor-β *A net proinflammatory response that may contribute to metabolic disease occurs with increased secretion of adipose tissue proinflammatory factors, and/or decrease in secretion of anti-inflammatory adipose tissue factors.

perspective, survey studies have suggested that the selfreported diagnosis of metabolic syndrome is often inaccurate and misunderstood [287]. The lack of universally accepted terminology to describe the interrelationship between excessive body weight and metabolic abnormalities is unsatisfying. This is especially so given analyses supporting the theory that the components of the metabolic syndrome are likely due to a unified pathophysiologic process [288], sometimes described as a ‘common soil’ hypothesis [289,290]. Pathogenic adipose tissue represents such a unified pathophysiologic process leading to metabolic diseases, which are often major CVD and CHD risk factors, and possibly leading directly to atherosclerosis itself [1,7,47,169,272,406] . Other terms have been proposed to better define the relationship of pathogenic adipose tissue to metabolic disease. One such term is adiposopathy (‘adipose-opathy’) [1,7,9,47,169,213,223,274,291–294,406,407], which is defined as pathogenic adipose tissue that is promoted by positive caloric balance and sedentary lifestyle in genetically and environmentally susceptible patients. Adiposopathy is anatomically manifested by adipocyte hypertrophy, visceral adipose tissue accumulation and ectopic fat deposition. Physiologically, adiposopathy results in adverse metabolic and immune consequences resulting in clinical metabolic disease [169]. The suffix ‘-pathy’ is often used to describe anatomical abnormalities of body organs that result in clinical disease, such as cardiomyopathy, myopathy, encephalopathy, ophthalmopathy, retinopathy, enteropathy, nephropathy, neuropathy and dermopathy [9]. Cardiomyopathy is a term that describes pathologic enlargement of cardiac cells and heart leading to clinical disease. Enlargement of adipocytes and adipose tissue also leads to clinical disease. Myopathy is a term that describes the pathologic dysfunction of muscle. Muscle cell hypertrophy is found in some types of muscular dystrophies. Muscle is an organ located in widespread locations in the body, with differing types of muscle having differing physiology and differing pathogenic potentials, depending upon the muscle type (skeletal, smooth and cardiac). Adipocyte hypertrophy and visceral fat accumulation are also pathogenic. Furthermore, similar to muscle, adipose tissue is located in widespread locations in the

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Review

body, with differing depots having different physiology and differing pathogenic potentials depending upon the depot (visceral, subcutaneous or perivascular). Adiposopathy describes adipocyte and adipose tissue anatomical abnormalities accompanied by pathophysiologic metabolic and immune responses that lead to metabolic illnesses. It is the ‘pathos’ of adipose tissue that helps to explain why the increasing epidemic of obesity is associated with an increased prevalence of T2DM, hypertension and dyslipidemia. The term adiposopathy highlights that adipose tissue has no less pathogenic potential than the pathos or pathologic dysfunction of other body organs and clinically represents no less of a ‘disease’ [9]. Another term that attempts to define the relationship between excessive fat mass and metabolic disease is ‘diabesity’, which represents an interpretation of a relationship between obesity and T2DM [295,296]. ‘Acquired lipodystrophy’ describes how the pathogenic potential of adipose tissue may be expressed by positive caloric balance through adipocyte hypertrophy-induced impairments of adipocyte functions. This is, paradoxically, not unlike the physiologic processes responsible for the adverse metabolic consequences associated with too little adipose tissue, as found with genetic lipoatrophy [35]. Finally, ‘Cushing’s disease of the omentum’ is a term describing the relationship between visceral fat and metabolic disease [9,27,81,102,297–302]. Five-year view: treatment of pathogenic adipose tissue to reduce CHD & CVD risk

No currently approved treatment indications exist for treatment of the non-mass-related consequences of pathogenic adipose tissue. However, therapies that improve pathogenic adipose tissue function may also improve clinical disease [47]. One of the most important reasons to consider adipocyte hypertrophy and visceral adipose tissue accumulation as a viable treatment target is because their pathogenic potential is modifiable. Treatment modalities that favorably modify pathogenic adipose tissue include nutritional interventions, increased physical activity [47,303,304] and drug therapy [293,47]. Acute caloric deprivation, such as through starvation or use of very low calorie meals, promptly improves many metabolic parameters associated with metabolic diseases [47]. These benefits may occur even before significant changes in overall fat mass, and are likely due to acute gene-expression responses of adipose tissue and other body organs [305,306]. The more clinically relevant gradual reduction in fat mass [47] through nutritional interventions [307–309] may favorably modify adipocyte size and gene expression [310]. Clinical observations support that it is not nutrition or physical activity, but rather weight (fat) loss that has the strongest effect upon reducing the risk of T2DM and dyslipidemia [311,312], especially when accompanied by a reduction in visceral adipose tissue [313]. Overall, nonpharmacological interventions that reduce adipocyte hypertrophy and reduce visceral adiposity improve glucose metabolism [314–317], hypertension [318,319] and dyslipidemia [316,320,321]. Not only

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are these therapeutic interventions effective for improving established disease, but regular physical activity [322] and weight loss in overweight and obese patients can also help delay and/or prevent the onset of T2DM, hypertension, and dyslipidemia [323,324,]. Pharmacologically, therapeutic agents such as PPAR-γ agonists are effective in treating metabolic diseases such as T2DM, with some PPAR agonists also improving some atherogenic lipid parameters [325]. The metabolic benefits of PPAR agonists are significantly due to their effects in promoting the recruitment of additional adipocytes and in improving the function of existing fat cells [31,47,326]. This may help to explain why administration of PPAR-γ agonists to patients with impaired glucose tolerance or impaired fasting glucose reduces the progression to T2DM [327]. Thus, PPAR-γ agonists promote the recruitment and proliferation of adipocytes, and decrease the ratio of visceral to subcutaneous adipose tissue. This helps resolve the apparent paradox wherein adding more (functional) adipose tissue is employed as a therapeutic strategy to improve metabolic disease, which in turn, is significantly due to too much (dysfunctional and pathogenic) adipose tissue [47,169]. Improving adipose tissue functionality has also been suggested to contribute to the favorable clinical outcomes found with common therapeutic agents such as ACE inhibitors and ARBs [7,83,84,328], as well as statins [329]. Finally, favorable effects upon both adipose tissue anatomic and metabolic parameters are found with the use of antiobesity, weight-loss agents [293] such as orlistat, sibutramine and cannabinoid receptor antagonists (not yet approved in the USA [291]). Improvements in adipocyte and adipose tissue function help explain why these agents improve metabolic disease [7,9,47]. Finally, the pathological consequences of adipocyte hypertrophy and visceral adipose tissue accumulation go far beyond the metabolic diseases highlighted in this review. Pathogenic adipose tissue may also contribute to hepatosteatosis [169,215], cancer [330], thrombosis, polycystic ovarian syndrome [331,332], hyperandrogenemia in women [1,119,331,333], hyperestrogenemia in men [1] and other metabolic abnormalities. Since adipose tissue health

Bays H, Ballantyne C. Adiposopathy: why do adiposity and obesity cause metabolic disease? Future Lipidol. 1(4), 389–420 (2006).

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Pathogenic adipose tissue may contribute to Type 2 diabetes mellitus, hypertension, dyslipidemia and atherosclerosis.

Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. Prevalence of overweight and obesity among US children, adolescents, and adults, 1999–2002. JAMA 291(23), 2847–2850 (2004).

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Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Adipocyte hypertrophy and visceral adiposity may contribute to metabolic diseases, such as Type 2 diabetes mellitus, hypertension and dyslipidemia. • The pathogenic potential of adipose tissue is dependent upon genetic and environment factors. • Impaired adipogenesis during positive caloric balance may lead to adipocyte hypertrophy, which contributes to metabolic disease, especially if it occurs in the visceral region. • The pathogenic potential of adipose tissue is not only dependent upon how the fat is stored (hypertrophy versus hyperplasia), but also where the fat is stored (visceral versus subcutaneous distribution). • Adipose tissue has important endocrine and immune activities whose disruption may lead to metabolic disease. • The net release of free fatty acids is a potential adverse consequence of pathogenic adipose tissue, which may contribute to metabolic disease. • The pathogenic potential of adipose tissue is best viewed as a partnership with the inherited or acquired limitations in ‘cross-talk’ and/or impairments of other body organs.

Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 288(14), 1723–1727 (2002).

Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA 298(17), 2028–2037 (2007).

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Donald A Bergman, MD 1199 Park Ave Suite 1F, New York, NY 10128-1713, USA Tel.: +1 212 876 7333 Fax: +1 786 549 7879 [emailprotected]

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J Michael González-Campoy, MD Minnesota Ctr for Obesity, Met. & Endo. (MNCOME), 880 Blue Gentian Road, Suite 150, Eagan, MN 55122, USA Tel.: +1 651 379 1613 Fax: +1 651 379 1650 [emailprotected]

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