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Circulation Topic Review
Ectopic Fat Depots and Cardiovascular Disease
Kathryn A. Britton, MD; Caroline S. Fox, MD, MPH
O
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besity is increasingly recognized as a heterogeneous
condition with variable cardiovascular risk in the setting
of similar levels of body mass index. Ectopic fat depots may
contribute to obesity-mediated vascular disease and explain
part of this risk differential. This review will explore the
current understanding of the biology of ectopic adipose tissue
storage, its quantification and classification, and existing
research supporting an association between ectopic fat and
cardiovascular disease.
Obesity is associated with significant cardiovascular morbidity and mortality, and is recognized as a major public
health concern.1,2 Although useful clinically and in epidemiologic studies, the classification of obesity using body mass
index (BMI) does not fully encompass the complex biology
of excess adiposity. Excess body fat is now recognized as a
heterogeneous condition in which individuals with similar
levels of BMI may have distinct metabolic and cardiovascular
disease risk.2 Variation in body fat distribution provides 1
potential explanation for some of the risk differential that
persists after accounting for BMI and standard risk factors.3
The study of ectopic adipose tissue depots, which surround
organs and blood vessels, focuses on the quantification of
these different fat depots and their potential systemic and
local consequences.
Waist circumference was one of the earliest means of
quantifying body fat distribution, and some clinical guidelines have recommended measurement of waist circumference to provide additional information regarding cardiovascular risk.4 However, waist circumference consists of both
subcutaneous adipose (SAT) (classically nonectopic) and
visceral adipose tissue (VAT) (classically ectopic). This is
important because VAT is associated with more adverse
levels of metabolic risk factors compared with SAT.5 In
addition, seminal work in mice has shown that transplantation
of SAT, but not VAT, to an intra-abdominal site resulted in
beneficial effects on metabolism.6 Taken together, these
findings suggest that information about body fat distribution
beyond waist circumference may provide important insights
into metabolic and cardiovascular disease risk.
defined by excess adipose tissue in locations not classically
associated with adipose tissue storage. There are several
potential mechanisms that might explain the tendency to
deposit adipose tissue in ectopic versus nonectopic depots.
One hypothesis suggests that, in states of positive energy
balance, excess free fatty acids are initially stored subcutaneously, but once the capacity of SAT is reached, storage
shifts to ectopic sites, including the viscera, heart, and
vasculature.9,10 The most extreme manifestation of this results
in lipodystrophy, characterized by a paucity of subcutaneous
fat with resultant deposition ectopically. This failure of SAT
to store additional free fatty acids is believed to result from a
failure of proliferation and differentiation of adipocytes
leading to subcutaneous adipose hypertrophy as opposed to
hyperplasia.10,11 Consistent with this theory, the degree of
subcutaneous abdominal adipose cell hypertrophy has been
shown to predict the development of type 2 diabetes mellitus.11 In addition, thiazolidinediones, which improve insulin
sensitivity, have been shown to promote differentiation of
new fat cells in subcutaneous fat without an increase in
visceral fat.12 Taken together, these data suggest that ectopic
fat deposition may result from the failure of SAT to act as a
metabolic sink.13
The determinants of subcutaneous versus ectopic fat are
likely multifactorial, and include age, sex, race, smoking,
nutritional and other environmental factors, and genetic
factors.13 One newly appreciated contributor is the angiogenic
capability of SAT. Recent work has shown that, in general,
SAT has a higher ability than VAT to expand its capillary
network.14 Specifically, SAT explants developed more capillary branches in comparison with VAT explants, and demonstrated a higher rate of growth when observed in culture. In
addition, SAT from insulin-sensitive individuals demonstrated higher expression of genes known to be associated
with angiogenesis. However, this greater angiogenic capacity of SAT decreased as BMI increased from the
overweight to obese range, and this decrease was associated with adverse metabolic features. This lower angiogenic capacity of SAT with increasing BMI may contribute
to the lower adipose tissue blood flow demonstrated in
SAT in the setting of obesity.15 This decreased blood flow
was associated with hyperoxia, as opposed to hypoxia, and
may reflect decreased oxygen consumption in SAT with
the development of obesity.
The growing appreciation of the potential importance of
ectopic fat depots in cardiovascular risk has led to interest in
more direct quantification of the different adipose tissue
depots. Multidetector computed tomography (MDCT), MRI,
ultrasonography, and 1H magnetic resonance spectroscopy
have all been used to quantify adipose tissue amount or lipid
content within an organ (Table). There are advantages and
disadvantages with each of these techniques. The ability to
Definition, Pathophysiology, and
Quantification of Ectopic Fat Depots
Some amount of adipose tissue surrounds several organs and
has been shown to serve a physiological role.7,8 Ectopic fat is
From the Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA (K.A.B.); and
the Circulation Editorial Office, Boston, MA (C.S.F.).
Correspondence to Caroline S. Fox, MD, MPH, Circulation Editorial Office, 560 Harrison Avenue, Boston, MA 02118; E-mail
[email protected].
© 2011 American Heart Association, Inc.
(Circulation. 2011;124:e837-e841.)
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.111.077602
e837
e838
Table.
Circulation
Imaging Modalities for Assessment of Ectopic Fat
Imaging Modality
Ultrasound
Multidetector Computed
Tomography (MDCT)
Magnetic Resonance
Imaging (MRI)
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1
December 13, 2011
H Magnetic Resonance
Spectroscopy
Ectopic Fat Imaged
Advantages
Disadvantages
• Epicardial/Pericardial
• Fatty Liver
• Extremely safe
• Relatively inexpensive
• Widely available
• Often performed for other clinical
indications
• Pericardial fat is only measured over the right ventricle.
This does not take into account variations in fat
deposition over the heart surface
• Obesity may limit image quality
• Fatty liver assessment is less quantitative than other
methods
• Sensitivity and specificity of fatty liver lower than other
methods
• Pericardial
• Pericoronary
• Thoracic Periaortic
• Visceral
• Fatty Liver
• Renal Sinus
• Easy to perform
• Often performed for other indications
• Allows volumetric assessment of adipose
tissue
• Submillimeter resolution
• Excellent reproducibility
• Can assess multiple fat depots
• Radiation exposure
• May not be able to accommodate individuals with
severe obesity
• Pericardial
• Visceral
• Perivascular
• Intra-hepatic
• Renal sinus
• Intra-muscular
(skeletal)
• Gold standard in assessment of visceral
adipose tissue
• No radiation or iodinated contrast required
• Can assess multiple fat depots
• More expensive than either MDCT or echocardiography
• Exam more time consuming and less tolerated by
patients
• May not be able to accommodate individuals with
severe obesity
• Intra-myocardial
• Intra-hepatic
• Intra-pancreatic
• Intra-muscular
(skeletal)
• Can measure lipid content within an organ
• Noninvasive
• No radiation or iodinated contrast required
• Most reliable imaging quantification
method for these fat depots
• Not currently used clinically
• Uncommonly performed for other indications
quantify adipose tissue depots noninvasively has led to an
increase in population-based analyses examining the association of various fat depots with both systemic and local
manifestations of disease.5,16 –18 These studies have taken the
knowledge of fat depot-specific biology gleaned from basic
and translational science and examined associations on a
population level.
Classification and Subtypes of Ectopic Fat
Ectopic fat depots can be subdivided based on their location
and their association with either potential systemic or local
effects (Figure). Ectopic fat depots with predominantly systemic effects include VAT, intrahepatic fat (also known as
fatty liver), and intramuscular fat. Ectopic fat depots with
potential local effects include pericardial (or the related
epicardial or pericoronary fat), renal sinus fat, myocardial
steatosis, and perivascular fat.
Alternatively, VAT may not be causally related to the
development of metabolic disease, but it may serve as a
marker of fat deposition in other ectopic locations. The
accumulation of adipose tissue in organs integral to glucose
and insulin metabolism (the liver and muscle) and lipid
metabolism (the liver) are then directly postulated to contribute to the development of metabolic derangements.20,21 Although intrahepatic fat and intramuscular fat have a volume
that is much smaller than VAT, they may have systemic
effects that contribute to systemic metabolic disease.20,21
However, the relative importance of these various fat depots
and their contributions to systemic metabolic derangements
remain unclear, and is an active area of investigation.
Findings from population studies have provided additional
insights into the associations of ectopic fat depots with
Ectopic Fat Depots With Predominantly
Systemic Effects
Although the association between obesity, body fat distribution, and metabolic derangements is now well established, the
underlying mechanisms remain incompletely understood.13
Ectopic fat depots play an important role in several of the
hypotheses postulated to explain the association of body fat
distribution and cardiovascular disease.13 First, with the
development of obesity, VAT becomes infiltrated with macrophages, and there is upregulation of a variety of adipokines.19 These adipokines have been shown to be important in
the development of inflammation and insulin resistance.19
Figure. Ectopic fat depots and their potential systemic and local
effects.
Britton and Fox
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predominantly systemic effects and cardiovascular disease.
Although both SAT and VAT are associated with adverse
metabolic risk factors, only VAT remains an important
correlate of risk after accounting for indices of generalized
adiposity.5 Another important finding is the sexual dimorphism present in body fat distribution and the consistent
findings that VAT is more strongly associated with metabolic
risk in women as compared to men. Inflammation and
oxidative stress may additionally contribute to the associations of both SAT and VAT with metabolic risk factors, and
both of these fat depots were associated with measures of
inflammation and oxidative stress.22 Although VAT was
more strongly associated with urinary isoprostanes and
monocyte chemoattractant protein-1, VAT and SAT demonstrated generally equivalent associations with circulating
biomarkers of inflammation. Taken together, these findings
suggest that circulating markers of inflammation are unlikely
to explain the excess risk associated with VAT in comparison
with SAT.
Population-level studies have also provided support for the
potential importance of fatty liver in the development of
insulin resistance and the metabolic syndrome.23,24 In adults,
fatty liver assessed by MDCT was associated with markers of
lipid and glucose metabolism, including insulin resistance,
even after adjustment for VAT.23 Similarly, in overweight
and obese children, metabolic syndrome was associated with
the presence of biopsy-proven fatty liver even after matching
for age, sex and the degree of obesity, and adjustment for
race, ethnicity, and hyperinsulinemia, as well.24 Although
these findings are intriguing, their observational nature precludes inferences of causality. Additional research is necessary to further delineate the relationship between VAT and
other ectopic fat depots with potential systemic effects and
their role in the development of metabolic disease.
Ectopic Fat Depots With Predominantly
Local Effects
In contrast to the ectopic fat depots with predominantly
systemic metabolic effects, fat depots surrounding the heart
and blood vessels and within the renal sinus are postulated to
have primarily local effects. The theory of a local toxic effect
of excess adipose tissue is supported by multiple lines of
evidence from basic science, translational science, and epidemiology.7,16,17,25–30 This idea of a direct effect of adiposity
on an organ was postulated in the early 20th century, and this
theory has gained renewed interest with the increased availability and technological advances in imaging techniques.
Increasing body weight may directly influence the heart by
at least 2 mechanisms. These include accumulation of adipose
tissue surrounding the heart and coronary arteries, or via lipid
accumulation within cardiomyocytes. Adipose tissue surrounding the heart, called epicardial or pericardial fat, encases the coronary arteries, and is therefore a subtype of the
perivascular adipose tissue that surrounds blood vessels.
Previous translational work has shown that perivascular
adipose tissue possesses anticontractile properties, and secreted substances, including adiponectin and the adipocytederived relaxing factor, play a role in the vasoactive properties of perivascular fat.7,8 However, this anticontractile
Ectopic Fat Depots and Cardiovascular Disease
e839
property of perivascular adipose tissue is abolished with the
development of obesity.7 Furthermore, in animal models,
obesity appears to reduce the physiological effect of perivascular fat on smooth muscle migration.31 These derangements
in the function of perivascular fat appear to be related to
infiltration of the adipose tissue by macrophages and upregulation of inflammatory adipokines.27 Consistent with this
finding, epicardial fat harvested at the time of coronary artery
bypass surgery was found to have higher levels of proinflammatory mediators in comparison with subcutaneous fat.29
Population level research has supported the idea of a local
toxic effect of pericardial fat. In the Framingham Heart
Study, the volume of pericardial fat was associated with
coronary artery calcium, but not cardiometabolic risk factors
(after VAT adjustment).25 By contrast, VAT, which can be up
to 20 times the volume of pericardial fat, was not associated
with coronary artery calcium.25 Similarly, pericardial fat was
found to be associated with incident coronary heart disease in
the Multi-Ethnic Study of Atherosclerosis.32 Additional work
examining associations of pericardial fat with measures of
cardiac structure and function, and clinical cardiovascular
disease, have shed further light on the idea of a local effect of
pericardial fat.16,26 First, pericardial fat volume assessed by
MDCT was found to be positively associated with MRImeasured left atrial size in men.16 Subsequent work supported
these findings by demonstrating a positive association between pericardial adipose tissue and prevalent atrial fibrillation,26 which is known to be associated with left atrial size.33
By contrast, although pericardial fat was associated with left
ventricular mass, this association did not persist after additional adjustment for VAT.16 These findings suggest that the
systemic effects of obesity appear to outweigh any local
effect of pericardial fat in the case of left ventricular mass.
In addition to adipose tissue surrounding the coronary
arteries, intramyocardial lipid accumulation represents another manifestation of ectopic fat storage that may lead to a
local adverse effect on the heart.28,30 With the use of in vivo
1
H magnetic resonance spectroscopy, higher amounts of
cardiac steatosis have now been observed among individuals
with impaired glucose tolerance and type-2 diabetes mellitus
in comparison with individuals who are lean.30 It is appropriate that debate has remained as to whether cardiac steatosis
is merely a marker of metabolic disturbances or alternatively
contributes directly to the development of cardiac dysfunction. To try to disentangle this issue, investigators used 1H
magnetic resonance spectroscopy and found increases in
intramyocardial lipid content after high-fat feeding in both
wild-type mice and a mouse model of elevated triacylglyceride.28 Not only did the transgenic mice demonstrate more
lipid accumulation, but the increase in intramyocardial lipids
was not solely triglycerides. In addition, after high-fat feeding, the transgenic, but not wild-type, mice demonstrated a
reduction in systolic strain as assessed by cardiac-tagged MRI
strain techniques. Overall, these findings support the possibility of a causal relationship between intramyocardial lipid
accumulation and cardiac dysfunction.
The possibility of local associations between a specific
ectopic adipose depot and its respective organ has also been
extended to thoracic periaortic fat and renal sinus fat. The
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Circulation
December 13, 2011
association of thoracic periaortic fat, a subtype of perivascular fat, and peripheral artery disease, is yet another example of
a potential local toxic effect of an ectopic fat depot.17
Thoracic periaortic fat is hypothesized to serve as a marker of
perivascular fat. Its association with peripheral arterial disease persisted despite adjustment for measures of generalized
and visceral adiposity, as well as adipokines. Renal sinus fat
has been postulated to affect kidney function by compressing
blood vessels as they exit the kidney.34 Consistent with this
hypothesis, renal sinus fat was found to be associated with
both hypertension and chronic kidney disease even after
adjustment for cardiovascular risk factors, including VAT.35
Unanswered Questions and Future Directions
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Although our understanding of ectopic fat depots has increased substantially in the past decade, the current body of
work has uncovered areas of uncertainty. Driven by the basic
science and translational literature, epidemiological studies
have demonstrated associations between unique fat depots
and cardiovascular disease. Further basic science and translational work will help clarify whether causal relations drive
these associations. Many of the basic science studies to date
have been limited to animal models. These will continue to be
crucial to our understanding of ectopic fat depots, but
additional investigations in human subjects will also be
essential. Studies comparing and contrasting the different
subtypes of ectopic fat have already highlighted important
similarities and differences, and will continue to provide
important insights. Further understanding of the effect of
weight loss on specific fat depots will be equally important.
Finally, an emerging body of work has begun to examine the
genetics of body fat distribution. For example, previous work
has identified 14 loci for body fat distribution independent of
BMI,36 and a common variant of the FTO gene has been
shown to be associated with the development of higher
amounts of both subcutaneous and visceral adiposity.37
Conclusion
Obesity will remain one of the most important worldwide
public health challenges.1 Additional research on adipose
tissue biology and ectopic fat will better identify individuals
at risk for cardiovascular disease morbidity and mortality. In
addition, a further understanding of the mechanisms potentially contributing to obesity-associated vascular disease may
eventually lead to novel therapies. The study of ectopic fat
depots and their association with metabolic risk factors and
vascular disease has provided some insight in this area, but
much additional work remains, and important advances are
anticipated in the coming years.
Acknowledgments
The authors thank Rose Thompson for artistic assistance in the
creation of the figure.
Sources of Funding
Dr Britton was supported by a Research Career Development Award
(K12 HL083786) from the NHLBI.
Disclosures
None.
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KEY WORDS: obesity
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risk factors
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imaging
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cardiovascular diseases
Ectopic Fat Depots and Cardiovascular Disease
Kathryn A. Britton and Caroline S. Fox
Circulation. 2011;124:e837-e841
doi: 10.1161/CIRCULATIONAHA.111.077602
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