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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
hbaysmd@aol.com
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 assoc-
iated 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%
• 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 physio-
logic benefits versus its potential pathogenic
contributions to ill health. A sole focus on fat
mass is often inadequate in assessing the assoc-
iated health risks of adipose tissue since being

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 Review Bays, González-Campoy, Bray et al.
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 mortal-
ity, and while combined overweight and obesity is associated
with increased mortality from T2DM and kidney disease, com-
parisons 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 adi-
pose 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 thera-
peutic cut-off points dependent upon the presence of
comorbidities [404]. However, given that the increase in meta-
bolic disease with increasing BMI is both continuous and grad-
ual [5,6], specific cut-off points may not apply to individual
patients, particularly when potential ethnic and gender vari-
ances 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 tis-
sues or cells, resulting in adverse clinical outcomes [9]. If adipo-
cyte hypertrophy and visceral adipose tissue accumulation
occur during positive caloric balance, then the pathogenic con-
sequences may unfavorably affect other body organs, such as
liver, muscle and pancreas, resulting in adverse clinical out-
comes [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
344
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 con-
sequences 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 proinflamm-
atory 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 abil-
ity 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 pre-
disposed, it is pathogenic adipose tissue that often ‘triggers’ the
expression of metabolic disease. In fact, it is because the patho-
genic 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 patho-
genic 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). Gluco-
corticoids are normally anabolic in the liver, causing increased
gluconeogenesis and increased glucose release. Hypercortisol-
ism may also increase the appetite of patients, often resulting in
positive caloric balance. Conversely, glucocorticoids are cata-
bolic to muscle, causing muscle wasting and insulin resistance,
and catabolic to adipose tissue, where lipolysis is modestly
Expert Rev. Cardiovasc. Ther. 6(3), (2008)

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 gluco-
corticoid 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 gluco-
corticoid-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 tis-
sue 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 glucocorti-
coid-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, macro-
phages and preadipocytes. During positive caloric balance,
increased storage of energy optimally occurs through the gener-
ation of added, functional fat cells, achieved through adipo-
genesis 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 cir-
culating free fatty acids often results in ‘lipotoxicity’ [31]. Lipo-
toxicity 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. Surg-
ical 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 hyper-
trophy, sometimes described as ‘acquired lipodystrophy’[35,36].
During positive caloric balance, adipocytes initially undergo
www.future-drugs.com
Pathogenic adipose tissue Review
hypertrophy, which normally triggers adipose tissue paracrine
adipogenic signaling for the purpose of adding functional fat
cells and towards maintaining adipose tissue physiologic func-
tions 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’ pre-
destined individuals to be lean or obese. However, this is no
longer thought to be true [40]. Not only does adipocyte hyper-
trophy 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 adipo-
cyte 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, dur-
ing times of positive caloric balance, if energy is stored predomi-
nantly through lipogenesis and fat cell hypertrophy of existing
adipocytes, as opposed to adipogenesis with recruitment and dif-
ferentiation 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) remodel-
ing 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 adi-
pose tissue growth, limits fat storage within adipose tissue and
increases the potential for ectopic fat storage, which may contrib-
ute to metabolic diseases [31]. Furthermore, while adipogenesis
may trigger ECM formation, adipocyte ECM factors may like-
wise affect adipogenesis [64]. If the appropriate and orderly forma-
tion of ECM is impaired, then this may also impair adipogenesis
and thus contribute to adverse clinical consequences of patho-
genic adipose tissue [35,52]. Similarly, an increase in adipose tissue
345
 Review Bays, González-Campoy, Bray et al.

growth also requires additional blood supply. If angiogenesis is

Box 1. Examples of factors
impaired, then relative hypoxia may impair adipogenesis [65],
influencing adipogenesis.
which exacerbates adipocyte metabolic dysfunction, and may
promote a net proinflammatory response [66–68], all contributing Modulating and transcriptional factors produced
to metabolic disease. by adipocytes
Thus, adipogenesis is a process that helps explain the seem- • Adipocyte determination and differentiation factor-1/
ingly paradoxical finding wherein not all overweight patients sterol regulatory element-binding proteins
have metabolic disease and not all patients with metabolic dis- • CCAAT/ enhancer-binding proteins
ease are significantly overweight [1,2,5,69,70]. During positive
• Peroxisome proliferator-activated γ receptors
caloric balance, the development of metabolic disease is more
• E2F proteins
closely related to how the fat is stored (through adipocyte
• Cyclin D
hypertrophy versus hyperplasia) than simply the amount of fat
that is stored [1,44]. • Cyclin-dependent kinases
The determination as to whether adipocytes respond to pos- • Nuclear receptors, such as farnesoid X receptor, liver X receptor
itive caloric balance with hypertrophy versus hyperplasia is and retinoid X receptors
based upon genetic predisposition and the actions of multiple Extracellular matrix factors produced by adipocytes
regulatory factors (BOX 1) [30]. Some adipocyte and nonadipo-
cyte factors may have different effects within the adipogenic • Actin
process, such as differing effects upon proliferation (creation of • Bone morphogenic protein
new adipocytes from preadipocytes) versus differentiation • Collagen-binding protein (colligin)
(increased maturity and lipogenesis within existing adipo- • Collagens
cytes). Angiotensin II impairs proliferation in humans • Cystatin C
(although reports are inconsistent in rodents [71]) and promotes • Cysteine protease cathepsin S (CTSS)
differentiation [72–77]. Angiotensinogen impairs proliferation in • Fibroblast growth factor
humans (although reports inconsistent in rodents [71]) and pro-
• Fibronectin
motes differentiation [72–75,77]. Autotaxin/lysophosphatidic acid
• Gelsolin
promotes proliferation and impairs differentiation [78,79].
• Integrin
Catecholamines promote proliferation and impair differentia-
tion [80]. Glucocorticoids impair proliferation and promote • Laminin
differentiation [27,81]. Finally, epidermal growth factor impairs • Matrix metalloproteases
proliferation and promotes differentiation [82]. • Myosin
This has practical, clinical implications in that glucocorticoids • Nidogen (entactin)
increase the differentiation of existing adipocytes (especially vis- • Osteonectin (secreted protein acidic and rich in
ceral adipocytes) relative to subcutaneous, peripheral adipocytes, cysteine [SPARC])
while decreasing adipocyte proliferation. The resulting hyper- • Procollagen
trophy of visceral adipocytes, coupled with a decrease in the • Stromal cell-derived factor 1
recruitment of functional subcutaneous, peripheral adipocytes, • Tubulin
is a contributing cause of the T2DM, hypertension and dys- • Vimentin
lipidemia often found with hypercortisolemia [1,26,27]. Angio-
tensinogen/angiotensin II may unfavorably decrease adipo- Angiogenesis factors produced by adipocytes
genesis. Conversely, enhanced adipogenesis is one of the
• Adiponectin
proposed reasons why angiotensin-converting enzyme (ACE)
• Angiogenin
inhibitors and angiotensin II blockers may improve metabolic
disease, including T2DM [72]. Additionally, ACE inhibitors and • Angiopoietin-2
angiotensin II receptor blockers (ARBs) increase peroxisome • Autotaxin
proliferator-activated receptor (PPAR)-γ activity (which promotes • Endostatin
adipogenesis), and have other effects that may involve adipose tis- • Fibroblast growth factor
sue. ACE inhibitors and ARBs may also increase adiponectin lev- • Hepatocyte growth factor
els, increase translocation of glucose transporters, upregulate tyro- • Hypoxia inducible factor-1
sine phosphorylation of insulin receptor substrate-1 and enhance • Leptin
bradykinin and nitric oxide activities [7,73,83–88]. Finally, weight • Monobutyrin
gain is often associated with an increase in catecholamine activ- • Matrix metalloproteinases
ity, as may be mediated through increased circulatory and CNS
• Nitric oxide synthase
leptin levels [89]. An increase in catecholamines would be

346 Expert Rev. Cardiovasc. Ther. 6(3), (2008)

 Pathogenic adipose tissue Review

Box 1. Examples of factors Box 1. Examples of factors

influencing adipogenesis (cont.).
• Osteonectin (SPARC)
• Pigment epithelium-derived factor
• Plasminogen activator inhibitor-1
• Platelet derived growth factor
• Prostaglandin E2
• Prostaglandin I2 (prostacyclin)
• Tissue factor
• Transforming growth factor
• Vascular endothelial growth factor
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 (promotes differentiation)
• Estrogens
• F-Box proteins (such as S-phase kinase-associated protein
[Skp]2)
• Free fatty acids
• Galectin 12 (promotes differentiation)
• Hormone sensitive lipase
• Insulin-like growth factor
• Leptin (inconsistent reports in medical literature)
• Leukemia inhibitory factor (inconsistent reports in
medical literature)
• Lipin
• Lysophosphosphatidic acid (promotes differentiation)
• Macrophage colony stimulating factor
• Neuronatin
• Nitric oxide
• Phosphoinositide 3-kinase
• Plasminogen activator inhibitor-1 (inconsistent reports in
medical literature)
• Prolactin
• Resistin (inconsistent reports in medical literature)
• Retinoids (inconsistent reports in medical literature)
influencing adipogenesis (cont.).
Adipose tissue factors that inhibit adipogenesis
• Androgens (testosterone)
• Angiotensin II (inhibits preadipocyte recruitment)
• Angiotensin-converting enzyme (inhibits preadipocyte
recruitment)
• Angiotensionogen (inhibits preadipocyte recruitment)
• Autotaxin (inhibits differentiation)
• Ceramide
• Chemerin
• 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
• Plasminogen activator inhibitor (inconsistent reports in
medical literature)
• Pre-adipocyte factor-1
• Prostaglandin F2
• Resistin (inconsistent reports in medical literature)
• Resistin-like molecules
• Retinoids (inconsistent reports in medical literature)
• Transforming growth factor-β
• TNF-α
Other factors, not necessarily adipocyte in origin, that
facilitate adipogenesis
• Catecholamines (neurologic signaling promotes
adipocyte hyperplasia)
• Hormones
– Estrogens
– Ghrelin (inconsistent reports in the literature)
– Glucocorticoids (stimulates differentiation)
– Insulin
– Insulin growth factor-1
– Prolactin
– Thyroid hormone
• Lipoproteins (very-low-density lipoproteins)

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 Review Bays, González-Campoy, Bray et al.

often have more visceral adipose tissue than individuals of similar

Box 1. Examples of factors
weight and no metabolic disease [92]. Such clinical findings are
influencing adipogenesis (cont.).
explained by the different intrinsic activities of fat depots [74,94–100].
• Lipids Visceral adipose tissue accumulation is the fat depot most charac-
– Endocannabinoids (anandamide) terized as being associated with an increased risk of metabolic dis-
– Dietary fats ease [97,99,101–109]. This is whether the visceral adipose tissue accu-
– Free fatty acids mulation occurs by hypertrophy or hyperplasia [1,97,101–108,110,111].
– Prostaglandins (PGE2, PGI2, PGJ2)
Conversely, if subcutaneous, peripheral adipose tissue undergoes
• Proteins hyperplasia with a generation of smaller and more functional
– Plasminogen/plasmin
adipocytes, then this added functionality may attenuate or reduce
– Neuropeptide Y
the risk of metabolic disease [1,35,36,43,51,52,56,58,112].
– Protein kinase C (PKC-βI)
– Protein kinase C inhibitor Location is one of the more important reasons why different
fat depots have different pathogenic potential. Visceral adipose
Other factors, not necessarily adipocyte in origin, that tissue, which represents approximately 20% of total body fat,
impair adipogenesis secretes various adipocyte factors (such as free fatty acids) into the
• Androgens portal vein, which supplies 80% of the hepatic blood supply
(TABLE 1) [107]. Also, visceral adipose tissue is genetically predeter-
• Catecholamines (neurologic signaling decreases adipocyte
hypertrophy) mined [113] to have different functions than subcutaneous,
• Cytokines (such as TNF-α)
peripheral adipose tissue (which represents approximately 80%
of total body fat). For example, these two fat depots differ in the
• Flavonoids
production of bioactive molecules, the activity of various recep-
• Ghrelin (inconsistent reports in the literature)
tors and the enzymatic processes involved with fat metabolism
• Glucagon-like peptide-1
(TABLE 1) [47,114–116]. An important clinical implications of these
• Glucocorticoids (impairs proliferation) differences is that when corrected for the same age, men are at
• Growth factors higher CHD risk than women. Comparatively, men often store
– Epidermal growth factor, (which impairs proliferation and more fat in the visceral region, representing a so called ‘android’
promotes differentiation)
adipose tissue distribution [117,118]. An increase in visceral adipos-
– Fibroblast growth factor
ity promotes metabolic diseases that are important CVD and
– Platelet-derived growth factor
– Transforming growth factor-β
CHD risk factors (T2DM, hypertension and dyslipidemia).
– Tumor growth factor β Conversely, women often have increased adipose tissue accu-
• Interferon
mulation and increased adipocyte size within the peripheral,
subcutaneous region, representing a so called ‘gynoid’ adipose
• Interleukins
tissue distribution [119–122]. These gender differences in adi-
• Protein kinase C (PKC-delta)
pose tissue distribution, described since the 1940s [123], can
• Prostaglandins (PGF2)
be at least partially explained by the influences of sex hor-
mones [1,47,74] . Analogous to the effects glucocorticoids may
expected to increase adipocyte proliferation and lipolysis, and have on visceral adipose tissue distribution [1,26,74,124], sex
thus potentially attenuate progression to metabolic disease. How- hormones can also affect adipose tissue distribution. Andro-
ever, a leptin-mediated increase in catecholamines levels may also gens are associated with increased visceral adipose tissue distribu-
increase blood pressure. With this exception aside, the favorable tion, while estrogens are associated with increased peripheral,
influence of catecholamines on lipolysis and adipogenesis helps subcutaneous adipose tissue distribution [1,26,74,125,126].
explain why impairment of these favorable metabolic activities, Adipose tissue depots not only differ in their metabolic activ-
such as might occur through the dysfunction of the sympathetic ity, but also in the degree of their metabolic activity. Visceral adi-
nervous system, may contribute to obesity and T2DM [90]. pose tissue, such as intraperitoneal (omental, mesenteric and
umbilical), extraperitoneal (peripancreatic and perirenal), and
intrapelvic (gonadal/epidydimal and urogenital) adipose tissue
Fat storage have a higher degree of metabolic activity compared with sub-
The pathogenesis of metabolic diseases is significantly influenced cutaneous, peripheral adipose tissue (truncal, gluteofemoral, mam-
by not only how the fat is stored (hypertrophy versus hyperplasia), mary and inguinal) [47,101,127]. Some have suggested that subcuta-
but also where the fat is stored [91]. Patient populations described neous adipose tissue in the abdominal region has metabolic
as metabolically healthy (no metabolic disease), but obese, often activity, such as lipolysis and the release of inflammatory factors,
have less visceral adipose tissue distribution than obese patients between that of visceral and subcutaneous, peripheral adipose tis-
with metabolic disease [92,93]. Conversely, patients who are meta- sue [101,111,128–130]. Accordingly, subcutaneous, abdominal adipose
bolically obese (those with metabolic disease), but normal weight, tissue may contribute to worsening of CHD risk factors [131].

348 Expert Rev. Cardiovasc. Ther. 6(3), (2008)

 Pathogenic adipose tissue Review

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 Subcutaneous < visceral
production, thus promoting dyslipidemia and hyperglycemia

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 Subcutaneous < visceral
§
Adipocyte factors
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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 Review Bays, González-Campoy, Bray et al.

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, peri-
pheral adipose tissue [47,128,133]. Pericardial and perivascular adi-
pose tissue accumulation may directly promote CHD and
peripheral vascular disease [133–137]. It has traditionally been
assumed that atherosclerosis is exclusively the result of patho-
logic interactions of intralumenal processes within arterial
subendothelia. However, pathogenic pericardial and perivascu-
lar 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 bal-
ance, 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 adi-
pose 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
increasing leptin levels appears to be near maximal at physio-
logic levels [142]. This may be, at least in part, because the secre-
tion 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]. None-
theless, while further increases in leptin levels may potentially
reduce abnormalities of glucose and lipid metabolism [1], hyper-
leptinemia may increase blood pressure [1,89,144–149]. Subcutane-
ous adipose tissue is the major source of circulating leptin
because subcutaneous adipose tissue is quantitatively the larg-
est 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 sub-
cutaneous adipose tissue than visceral adipose tissue, then
hypertrophy of subcutaneous adipocytes may lead to hyperlep-
tinemia-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 subcuta-
neous 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, particu-
larly when accompanied by adipocyte hypertrophy, a relative
increase in visceral adipose tissue often has a greater blood pres-
sure-raising effect. This may possibly be due to the deleterious
effects of visceral adipose tissue upon various adipocyte factors

350 Expert Rev. Cardiovasc. Ther. 6(3), (2008)


(TABLE 1), such as IL-6, C-reactive protein and TNF-α, directly
leading to endothelial dysfunction [152]. Obesity-induced insu-
lin resistance may also impair the release of otherwise vasodila-
tory, 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 adi-
posity, 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 vis-
ceral 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 clini-
cal 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 proce-
dures most widely used to assess visceral fat depots [156], with
CT often considered to be the gold-standard imaging tech-
nique for assessing various fat depots [132,136,157–159]. MRI may
also provide good imaging for visceral adipose tissue and intra-
muscular fat, but perhaps less so for subcutaneous or inter-
muscular 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 vis-
ceral fat and, thus, more predictive of an increased risk of meta-
bolic 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 sug-
gested that BMI performs at least as well as waist circumference
in identifying the potential for insulin sensitivity abnormalities
and CHD risk factors [162].
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 secre-
tory product from adipose tissue is free fatty acids [29], which
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Pathogenic adipose tissue Review
are derived from the lipolysis of stored triglycerides, and regu-
lated by adipocyte and nonadipocyte factors (BOX 2). If intra-
cellular adipocyte hydrolysis of triglycerides (lipolysis) exceeds
intracellular adipocyte esterification of free fatty acids (lipo-
genesis), 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 metab-
olism due to ‘lipotoxic’ effects upon muscle and liver (con-
tributing to insulin resistance) [153] and pancreas (contribut-
ing 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 ‘gluco-
centric’ view of diabetes to an increasingly acknowledged
‘lipocentric’ viewpoint.’
Increases in circulating free fatty acids are also an independ-
ent risk factor for hypertension, possibly due to free fatty
acid-induced insulin resistance, which itself contributes to
high blood pressure [167,168]; impairment of endothelium-
dependent vasodilation [167,168]; and other microvascular dys-
functions leading to hypertension [167,168]. Finally, increases in
circulating free fatty acids contribute to the typical dyslipid-
emia found with the ‘metabolic syndrome,’ which includes
hypertriglyceridemia, reduced high-density lipoprotein-cho-
lesterol 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 tis-
sue are actively involved in metabolic processes such as angio-
genesis, adipogenesis, ECM dissolution and reformation, lipo-
genesis, growth factor production, glucose metabolism,
production of factors associated with the renin–angiotensin sys-
tem, lipid metabolism, enzyme production, hormone produc-
tion, steroid metabolism, immune response, hemostasis and ele-
ment binding (BOX 3). The disruption of these adipose tissue
processes, as occurs with adipocyte hypertrophy and visceral adi-
pose tissue accumulation, results in adipocyte factor abnormali-
ties that are not only associated with, but may be important
contributors to metabolic diseases (TABLE 2) [1,47,169].
Inflammation
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
351
 Review Bays, González-Campoy, Bray et al.

and significant amounts of other inflammatory factors,

Box 2. Examples of adipose tissue factors that
including interleukins, cathepsin S, macrophage-inhibitory
affect free fatty acid metabolism.
factor, nerve growth factor and inducible nitric oxide synthase
• Acetyl-coenzyme A carboxylase (iNOS) [178,181,188,189]. Furthermore, the origin of increases in
• Acetyl-coenzyme A synthetase inflammatory factors found in patients with excessive body
• Acylation-stimulating protein weight are often derived from nonadipose tissue [172,190], with
• Adenosine pathogenic adipose tissue promoting the inflammatory
• Adenosine monophosphate protein kinase (AMPK) responses from other body organs. An example would be hepatic
• Adiponutrin C-reactive protein production in response to adipocyte/adipose
tissue IL-6 release, as may occur with obesity [191].
• Adipophilin (adipose differentiation-related protein)
As previously described, adipocytes are metabolically active
• Adipsin (complement factor D)
and have the capacity to secrete nonproteins factors such as
• Adrenomedullin
prostaglandins, fatty acids, monobutyrin, and steroid hormones.
• Agouti protein From an immune standpoint, adipocytes and adipose tissue also
• Androgens produce bioactive proteins, termed adipokines, which are secre-
• Angiotensin I and II tory factors that include classic cytokines, complement factors,
• Angiotensinogen enzymes, growth factors, hormones and matrix proteins.
• Annexin Increased secretion of proinflammatory adipokines with
• Apolipoprotein C1 cytokine activity may contribute to metabolic disease, including
• Aquaporin 7 atherosclerosis [1,47,180,192]. Adipose tissue-derived inflammatory
• Carnitine palmitoyl transferase-1 factors that are potentially pathogenic include acute phase
• Caveolin reactants, such as plasminogen activator inhibitor-1 [193] and
possibly C-reactive protein [194,195], proteins of the alternative
• Desnutrin (adipocyte triglyceride lipase [ATGL])
complement system [1,47,172], chemotactic/chemoattractant adipo-
• Estrogens
kines [1,47], eicosanoids/prostaglandins [1,47], and reduced secretion
• Fasting-induced adipocyte factor
of anti-inflammatory factors (BOX 4) [1,47,192].
• Fatty acid-binding protein It is not known which, if any, proinflammatory factors are best
• Fatty acid synthase to measure in relation to adipose tissue’s promotion of metabolic
• Fatty acid translocase (CD36) disease. Among the more commonly described adipose tissue
• Fatty acid transport protein inflammatory factors associated with T2DM are TNF-α, IL-6 [196]
• Hormone sensitive lipase and C-reactive protein, which are all positively correlated to adi-
• Interleukins pocyte size [197]. Adiponectin is the adipocyte/adipose tissue anti-
• Leptin inflammatory factor whose decreased levels are best described to be
• Lipin associated with metabolic disease. Adiponectin levels are negatively
• Lipoprotein lipase correlated with adipocyte size [197].
• Perilipin
• Phosphoenolpyruvate carboxykinase (PEPCK) Cross-talk & interactions with other body tissues
• Prostaglandins
The onset or worsening of many metabolic diseases might best
• S3-12 be considered the net result of a pathologic partnership
• Stearoyl-CoA desaturase between adipose tissue and limitations and/or dysfunction of
• Tail interacting protein 47 other body organs. Impaired cross-talk with adjacent adipo-
• Transcription factors cytes, such as paracrine signaling [198], may account for impaired
• TNF-α adipogenesis and promotion of metabolic disease [199]. Cross-
talk is defined as biological signaling exchanges between body
that stimulate other tissues to produce inflammatory factors; organs. This cross-talk is important for the integration of meta-
and decreased production of anti-inflammatory factors [1,29]. bolic functions of adipocytes/adipose tissue with other adipo-
The net proinflammatory response associated with patho- cytes, other adipose tissue depots and other body organs. Dis-
genic adipose tissue is an important contributor to metabolic rupted or adverse cross-talk between adipose tissue and other
disease [1,166,180,183–187]. body organs may contribute to metabolic disease [200,201].
Adipose tissue inflammatory factors are produced by both Organs systems affected by signaling from adipose tissue
adipocytes and associated inflammatory cells, such as adipose include the nervous system [202], immune system [176], skele-
tissue-related macrophages. Adipose tissue macrophages may tal muscle [203–206], cardiovascular system [133,167,187,207–213]
be responsible for almost all adipose tissue TNF-α expression liver [214,215], gastrointestinal system [216], adrenal cortex [217]

352 Expert Rev. Cardiovasc. Ther. 6(3), (2008)

 Pathogenic adipose tissue Review

Box 3. Examples of adipose tissue properties that Box 3. Examples of adipose tissue properties that
highlight its activity as a metabolic organ. highlight its activity as a metabolic organ (cont.).
Receptors for traditional peptide and Catecholamine receptors
glycoprotein hormones
• Catecholamines such as α1 and α2; β1, β2, β3
• Adiponectin • Muscarinic receptors
• Angiotensin II type 1 and 2 • Nicotinic receptors
• Gastrin/cholecystokinin
• Glucagon
Other receptors
• Glucagon-like peptide-1 • Adenosine
• Growth hormone • Cannabinoids
• Insulin • Lipoproteins (high-density lipoprotein, low-density lipoprotein,
• Insulin-like growth factors very-low-density lipoprotein)
• Thyroid stimulating hormone • Melanocortins
• Neuropeptide Y
Receptors for nuclear hormones • Prostaglandins
• Androgens
• Estrogens and thyroid [218]. The best example might be the CNS [202,219–226],
• Glucocorticoids
which would include the CNS activity of leptin/insulin
[143,224,227–235], pro-opiomelanocortin (POMC)/cocaine ampheta-
• Nuclear factor-kB
mine-regulated transcript (CART) [223,229,236,237], neuropeptide Y
• Progesterone
(NPY)/agouti-related peptide (AgRP) [223,229,238–242], melano-
• Thyroid hormone
cortin system, [223,236,239,243–248] and CNS neuroendocrine activ-
• Vitamin D ity (e.g., thyroid-releasing hormone and corticotropin-releasing
Other nuclear receptors hormone) [223,249,250]. More recently, the endocannabinoid sys-
tem is becoming more recognized as playing an important role
• Peroxisome proliferator-activated receptor (PPAR) α receptors in adipocyte function, and the pathogenic potential of adipose
• PPAR β receptors tissue [7,223,251–259]. Abnormalities of other organ systems may
• PPAR δ receptors also affect the pathogenic potential of adipose tissue [260–262].
• PPAR γ receptors In addition to impaired cross-talk signaling, nonadipose body
• Farnesoid X receptors organs may have inherent or acquired dysfunction or limitations
• Liver X receptors that increase the risk of developing metabolic disease. Some
• Retinoid X receptors patients may have an inability to metabolize intramuscular fat due
to genetic or acquired ‘inflexibility’ in their oxidation of free fatty
Receptors for cytokines or adipokines with acids [263]. If fat cell hypertrophy and/or increase in visceral adi-
cytokine-like activity pose tissue results in increased circulating free fatty acids, this may
• Adiponectin cause excessive ectopic free fatty acid storage in muscle. Such
• Interleukins ‘lipotoxicity’ is pathogenic in that the accumulation of intramyo-
• Leptin
cellular lipids, such as diacylglycerol, fatty acyl CoA and cera-
mides, promote insulin resistance [263–267]. Fat weight loss through
• Transforming growth factor-β
hypocaloric nutritional intervention may not necessarily improve
• TNF-α
‘inflexible’ muscle’s inherent ability to metabolize free fatty acids.
Receptors for growth factors But such intervention is nonetheless therapeutic in that through
fat weight loss, the triglyceride content of skeletal muscle is
• Epidermal growth factor
reduced, improving insulin sensitivity [266]. Thus, in the presence
• Fibroblast growth factor of limitations or dysfunction of target organs, positive caloric bal-
• Hepatocyte growth factor ance may promote metabolic disease, while negative caloric bal-
• Insulin-like growth factor ance may improve metabolic disease. Conversely, if skeletal mus-
• Platelet-derived growth factor cle were to become ‘hyperflexible’ (i.e., develop an increased
• Transforming growth factor-β capacity to metabolize free fatty acids), either through genetic pre-
• Tumor growth factor disposition or through the use of drug therapies (such as PPAR-γ
• Vascular endothelial growth factor agents), then metabolic disease may be theoretically prevented or
improved [268], even in the presence of pathogenic adipose tissue.

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 Review Bays, González-Campoy, Bray et al.

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.

354 Expert Rev. Cardiovasc. Ther. 6(3), (2008)

 Pathogenic adipose tissue Review

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.

www.future-drugs.com 355
 Review Bays, González-Campoy, Bray et al.

The liver is also an important organ in oxidizing and metabo-

Box 4. Inflammatory factors associated with
lizing free fatty acids. With positive caloric balance, adipocyte
adipose tissue*.
hypertrophy and visceral adipose tissue accumulation may
increase the flow of free fatty acids to the liver, increasing Adipokines with cytokine activity
hepatic lipid content, and resulting in the common clinical • Adipsin
finding of hepatosteatosis (‘fatty liver’). Patients with ‘inflexibil-
• IL-1B, IL-6, IL-8, IL-17D, IL-18
ity’ in hepatic free fatty acid oxidization may be more suscepti-
• Leptin
ble to lipid accumulation in the liver and, thus, more prone to
• Macrophage colony-stimulating factor
developing insulin resistance and dyslipidemia [34]. Finally, in
patients with an inherent or acquired insulinopenia, the • Macrophage-inhibitor factor
chronic increase in circulating free fatty acid from pathogenic • Monocyte chemotactic protein-1
adipose tissue and ectopic free fatty acid deposition in the pan- • Regulated on activation, normal T-cell expressed and
creas may decrease insulin secretion and also contribute to secreted (RANTES)
T2DM [269]. • Resistin
In summary, adipose tissue does not act alone in its potential • TNF-α
to promote metabolic disease. In patients who are predisposed • Visceral adipose tissue-derived serpin
to metabolic disease due to genetic background, age [270], gen-
der, nutritional intake, physical activity level, comorbid condi- Acute phase reactants
tions, concurrent drug treatments and other predispositions, it • α-1 acid glycoprotein
is the limitation or dysfunction of other body organs that deter- • Amyloid A
mines the degree by which the pathogenic potential of adipose • Ceruloplasmin
tissue will promote metabolic disease. Thus, the variability in • C-reactive protein
fat weight gain which results in metabolic disease is not only • Haptoglobin
due to how fat is stored (adipogenesis), where the fat is stored
• IL-1 receptor antagonist
(visceral versus other fat depots), but is also dependent upon
• Lipocalins
the signaling and interactions with other body organs.
• Metallothionein
• Pentraxin-3
Adverse clinical consequences of excessive fat mass • Plasminogen activator inhibitor-1
Excessive fat mass alone may contribute to other clinical disor-
Adipokines of the alternative complement system
ders, such as cardiovascular [138,139,207,271–273], neurologic [138,139],
pulmonary [138,139,271], musculoskeletal [138,139], dermato- • Adipsin
logic [138,139], gastrointestinal, [138,139] genitourinary [138,139], • Acylation-stimulating protein
renal [138,139,272] and psychological diseases [138,139]. • Complements C3 and B

Chemotactic/chemoattractant adipokines
Expert commentary: defining pathogenic adipose • Eotaxin
tissue & its metabolic complications • Interferon inducible protein
Currently, the most common term defining the clustering of • Monocyte chemoattractant protein-1
metabolic abnormalities that increase atherogenic risk is the • Macrophage colony-stimulating factor
‘metabolic syndrome.’ The diagnostic parameters for metabolic • Macrophage migration inhibitory factor
syndrome include increased waist circumference, elevated fast-
• Stromal derived factor-1
ing glucose levels, elevated blood pressure, elevated triglyceride
• RANTES
levels and low HDL-C levels [169,272–277]. However, this term
• Resistin
does not reflect a description of the unified, pathophysiologic
process leading to these clustering of metabolic disorders. Nor • TNF-α
is there uniform agreement as to its definition [274,169]. Finally, • Vascular adhesion protein-1
the diagnosis of the metabolic syndrome may not be a better • Vascular cell adhesion molecule-1
predictor of future metabolic disease than assessment of its
Eicosanoids/prostaglandins
individual components [278–280]. Many (but not all) clinicians
find the term metabolic syndrome useful, [281–276,284–286] with • Prostaglandin E2
the hope that corralling key physical examination and labora-
*A net proinflammatory response that may contribute to metabolic disease
tory measures into a group may help better focus attention to occurs with increased secretion of adipose tissue proinflammatory factors, and a
parameters that increase CHD risk. However, from a patient decrease in secretion of anti-inflammatory adipose tissue factors.

356 Expert Rev. Cardiovasc. Ther. 6(3), (2008)


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 self-
reported diagnosis of metabolic syndrome is often inaccurate
and misunderstood [287]. The lack of universally accepted ter-
minology 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 tis-
sue 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 geneti-
cally 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 abnor-
malities of body organs that result in clinical disease, such as
cardiomyopathy, myopathy, encephalopathy, ophthalmo-
pathy, 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 differ-
ing types of muscle having differing physiology and differing
pathogenic potentials, depending upon the muscle type (skel-
etal, 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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Pathogenic adipose tissue 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 abnormali-
ties 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 epi-
demic of obesity is associated with an increased prevalence of
T2DM, hypertension and dyslipidemia. The term adipo-
sopathy 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 rep-
resents an interpretation of a relationship between obesity and
T2DM [295,296]. ‘Acquired lipodystrophy’ describes how the path-
ogenic potential of adipose tissue may be expressed by positive
caloric balance through adipocyte hypertrophy-induced impair-
ments 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 treat-
ment of the non-mass-related consequences of pathogenic adi-
pose tissue. However, therapies that improve pathogenic adi-
pose tissue function may also improve clinical disease [47]. One
of the most important reasons to consider adipocyte hyper-
trophy and visceral adipose tissue accumulation as a viable treat-
ment 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 depri-
vation, such as through starvation or use of very low calorie
meals, promptly improves many metabolic parameters associ-
ated 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 inter-
ventions [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, nonpharma-
cological interventions that reduce adipocyte hypertrophy and
reduce visceral adiposity improve glucose metabolism [314–317],
hypertension [318,319] and dyslipidemia [316,320,321]. Not only
357
 Review Bays, González-Campoy, Bray et al.

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 ago-
nists 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 recruit-
ment of additional adipocytes and in improving the function of
existing fat cells [31,47,326]. This may help to explain why admin-
istration 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 sug-
gested 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 antago-
nists (not yet approved in the USA [291]). Improvements in adi-
pocyte and adipose tissue function help explain why these
agents improve metabolic disease [7,9,47].
Finally, the pathological consequences of adipocyte hyper-
trophy 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], hyperandro-
genemia in women [1,119,331,333], hyperestrogenemia in men [1]
and other metabolic abnormalities. Since adipose tissue health
may affect patient health, clinicians should understand the
importance of pathogenic adipose tissue in the genesis of the
most common diseases encountered in medical practice, many
of which are important CVD risk factors. Scientific organiza-
tions should work towards a consensus to define, diagnosis and
eventually treat pathogenic adipose tissue.
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.

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