Etiology and Pathophysiology
Subcutaneous and visceral adipose tissue:
structural and functional differencesobr_623 11..18
M. Mohsen Ibrahim
Cardiology Department, Cairo University,
Cairo, Egypt
Received 14 January 2009; revised 10 May
2009; accepted 15 May 2009
Address for correspondence: MM Ibrahim,
Cardiology Department, Cairo University, 1
El-Sherifein Street, Abdeen, Cairo 11111,
Egypt. E-mail: ehs@link.net
Summary
Obesity is a heterogeneous disorder. Obese individuals vary in their body fat
distribution, their metabolic profile and degree of associated cardiovascular and
metabolic risk. Abdominal obesity carries greater risk of developing diabetes and
future cardiovascular events than peripheral or gluteofemoral obesity. There
are differences between adipose tissue present in subcutaneous areas (SCAT) and
visceral adipose tissue (VAT) present in the abdominal cavity. These include
anatomical, cellular, molecular, physiological, clinical and prognostic differences.
Anatomically, VAT is present mainly in the mesentery and omentum, and drains
directly through the portal circulaion to the liver. VAT compared with SCAT is
more cellular, vascular, innervated and contains a larger number of inflammatory
and immune cells, lesser preadipocyte differentiating capacity and a greater percentage
of large adipocytes. There are more glucocorticoid and androgen receptors
in VAT than in SCAT. VAT adipocytes are more metabolically active, more
sensitive to lipolysis and more insulin-resistant than SCAT adipocytes. VAT has a
greater capacity to generate free fatty acids and to uptake glucose than SCAT and
is more sensitive to adrenergic stimulation, while SCAT is more avid in absorption
of circulating free fatty acids and triglycerides. VAT carries a greater prediction of
mortality than SCAT.
Keywords: Adipokines, adipose tissue, fatty acids, obesity.
obesity reviews (2010) 11, 11–18
Aim of this review
• provides a better understanding of the structure and
function of adipose tissue as it relates to its distribution in
subcutaneous and visceral areas;
• describe the heterogenous nature of obesity and the
important differences between visceral and subcutaneous
adiposity;
• introduces the reader to modern basic science information
related to adipocyte physiology such as molecular
biology of adipose tissue, insulin resistance and regional fat
metabolism.
Introduction
It has been recognized for more than 60 years (1) that the
cardiovascular risk of obesity and increased body weight
are related more to body fat distribution rather than total
body fat. Individuals with upper abdominal, central or
android obesity are at a greater risk than those with
gluteofemoral, peripheral or gynoid obesity. Fat present
around abdominal viscera in mesentery and omentum,
known as visceral fat, is different from that present in
subcutaneous areas (subcutaneous fat). The type of fat cells
(adipocytes), their endocrine function, lipolytic activity,
obesity reviews doi: 10.1111/j.1467-789X.2009.00623.x
11© 2009 The Author
Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 11, 11–18
response to insulin and other hormones differ between
subcutaneous adipose tissue (SCAT) and visceral adipose
tissue (VAT). Inflammatory cells (macrophages) are more
prevalent in visceral compared with subcutaneous fat (2,3).
However this was not found by all investigators (4).
Subcutaneous fat accumulation represents the normal
physiological buffer for excess energy intake (highcaloric
diet) with limited energy expenditure (physical inactivity).
It acts as a metabolic sink where excess free fatty
acids (FFAs) and glycerol are stored as triglycerides (TGs)
in adipocytes (5). When the storage capacity of SCAT is
exceeded or its ability to generate new adipocytes is
impaired because of either genetic predisposition or stresses
(physiological and mental stress), fat begins to accumulate
in areas outside the subcutaneous tissue – the natural store
house for energy. Chronic stress leads to elevated cortesol
levels that may lead to accumulation of VAT (6).
The anatomical and physiological differences between
VAT and SCAT help explain the increased metabolic and
cardiovascular risks associated with abdominal obesity. It
is important to mention that the sequences proposed are
being hypothetical.
Anatomical differences
The main areas for subcutaneous fat deposition are the
femerogluteal regions, back and anterior abdominal wall.
About 80% of all body fat is in the subcutaneous area
(7,8). The abdominal fat is present in two main depots:
subcutaneous and intra-abdominal.
Intra-abdominal fat
Visceral fat accounts for up to 10–20% of total fat in men
and 5–8% in women (7). The amount of visceral fat
increases with age in both genders (7).
Portal drainage
Because of its anatomical position, visceral fat venous
blood is drained directly to the liver through the portal
vein. This contrasts with subcutaneous fat where venous
drainage is through systemic veins. The portal drainage
of visceral fat provides direct hepatic access to FFAs and
adipokines secreted by visceral adipocytes. Adipokines
activate hepatic immune mechanisms with production of
inflammatory mediators such as C-reactive protein (CRP)
(9,10).
Cellular differences
Structure of adipose tissue
The adipose tissue is made of a large number of adipocytes,
other non-fat cells, connective tissue matrix, vascular and
neural tissues. The non-adipocytes cellular component
includes inflammatory cells (macrophages), immune cells,
preadipocytes and fibroblasts.
Adipocytes
Adipocytes constitute the main cellular component of
adipose tissue and are the chief storage depots of the energy
in form of TG droplets. New smaller adipocytes act as a
sink or powerful buffers, which avidly absorb FFAs and
TGs in the postprandial period. As adipocytes grow larger,
they become dysfunctional. Large adipocytes are insulinresistant,
hyperlipolytic and resistant to anti-lipolytic effect
of insulin. VAT contains greater number of large adipocytes
in contrast to SCAT, which contains the small adipocytes.
Small adipocytes are more insulin-sensitive and have high
avidity for FFAs and TGs uptake, preventing their deposition
in non-adipose tissue (10,11).
Vascularity and innervation
Visceral adipose tissue is characterized by being more vascular,
rich in blood supply and more heavily innervated
than SCAT.
Molecular differences
• Receptors: adipose tissue cells are provided by receptors
that are activated by three types of signals (i) Chemical
signals in form of the circulating endocrine hormones
that reach adipocytes through bloodstream; (ii) Chemical
signals of biologically active molecules (adipokines) that
are generated locally in adipose tissue and activate the
neighbouring fat tissue cells through paracrine mechanisms
and (iii) Nervous signals in form of the nerve impulses
originating in the central nervous system and activating
specific adrenergic receptors in fat tissue e.g. b3-adrenergic
receptors and a2-adrenergic receptors.
• Adipokines: adipose tissue is capable of synthesizing a
number of peptides, proteins and cytokines. These biologically
active molecules are known as adipokines. Over 50
adipokines have already been identified (12).
Adipose tissue receptors
There are regional variations in the adipose tissue receptors
density, affinity and signal transduction.
Glucocorticoid receptors
Glucocorticoid receptors are involved in metabolic regulation
and distribution of body fat (13). They show regional
variation in density with elevated concentrations in VAT
(14).
12 Subcutaneous and visceral adipose tissue M. M. Ibrahim obesity reviews
© 2009 The Author
Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 11, 11–18
Androgen receptors
Androgen receptors have higher density in VAT adipocytes
than in adipocytes isolated form SCAT (5). After middle
age in men, with decline in testosterone, more fat is deposited
in VAT stores, and SCAT tends to decrease after age of
50 years (15).
Oestrogen receptors
Oestrogen receptors are expressed in human adipose tissue
(16) and show regional variation in density with gender
differences and greater binding capacity in SCAT (17).
Oestrogen promotes the accumulation of peripheral gluteofemoral
SCAT, which may be protective. Deficiency of
oestrogens contribute to increase in VAT in postmenopausal
women (5,15).
Adrenergic receptors
Abdominal visceral adipocytes, compared with subcutaneous
abdominal or femoral adipose cells, are more sensitive
to catecholamine-induced lipolysis and less sensitive to
a2-adrenergic receptor-dependent inhibition of lipolysis
(18,19).
Increased b3-adrenoreceptor sensitivity and a2adrenergic
receptor sensitivity to catecholamine stimulation
is present in VAT compared with SCAT (20). Level of
b3-adrenoreceptors is higher in VAT (21).
Adipokines and modern adipocyte physiology
Mature adipocytes act as an active endocrine and paracrine
organ and through a communication network with other
tissue, sympathetic nervous system and brain can influence
appetite, energy balance, immunity, insulin sensitivity,
angiogenesis, blood pressure, lipid metabolism and
homeostasis. Adipocytes contribute to the raised proinflammatory
state in obesity and diabetes. They are
capable of synthesizing pro-inflammatory and antiinflammatory
proteins. They secrete monocyte chemoattract
protein-1 that can induce macrophages infiltration
and activation in adipose tissue. Macrophages are important
source of inflammatory cytokines such as tumour
necrosis factor (TNF)-a and IL-6. New discoveries have
demonstrated the diversity of adipokines (12,22–24)
including classical cytokines, growth factors, protein
involved in vascular haemostasis, glucose haemostasis,
angiogenesis and acute phase responses. Six adipokines
were newly identified as secretary products of omental
adipose tissue (25): three chemokines (growth-related
oncogen factor, RANTES, macrophage inflammatory
protein-1B), one interlukin (IL-7), one tissue inhibitor of
metalloproteinases (TIMP-), and one growth factor
(thrombopoietin). The following is a summary of functions
of some important adipokines.
Leptin
• Signals the status of energy stores and its secretion can
reduce appetite and increase energy expenditure.
• Development of vasculature (angiogenesis).
• Production of red blood cells (haemotopoisesis).
• Immunity.
• Induce proliferation and migration of vascular smooth
muscle cells.
• Enhance platelet aggregation and arterial thrombosis.
• Obesity is associated with elevated leptin levels. Leptin
is a sensitive marker for predicting cardiovascular risk and
metabolic syndrome.
Adiponectin
• Anti-atherogenic: inhibits expression of adhesion molecules
and vascular smooth muscle cells proliferation and
suppresses transformation of macrophages to foam cells.
It induces the production of important anti-inflammatory
factors such as IL-10.
• Anti-diabetic: increases insulin sensitivity and
decreases hepatic glucose output. It increases fatty acid
oxidation.
• Adiponectin is decreased in abdominal obesity.
IL-6
• Proatherogenic: increase vascular inflammation.
• Prodiabetic: decrease insulin signalling.
• Major regulator of hepatic CRP production.
• IL-6 is increased is abdominal obesity; 30% of circulating
IL-6 originates from adipose tissue.
TNF-a
• Proatherogenic: increase vascular inflammation (activates
transcription factor nuclear factor-k B).
• Prodiabetic: decrease insulin sensitivity and insulin
signalling.
• TNF-a is increased in abdominal obesity.
CRP
• Proatherogenic: increase vascular inflammation.
• Correlates with metabolic syndrome.
• Prodiabetic: predict development of diabetes.
• CRP is increased in abdominal obesity.
Plasminogen activator inhibitor-1 (PAI-1)
• Proatherogenic: increase atherothrombotic risk,
increase thrombosis function.
Interactions between adipokines
Tumour necrosis factor-a and interlukins increase leptin
gene expression and circulating leptin levels (26,27).
TNF-a contributes to obesity-related hyperliptonemia by
regulating leptin release from adipocytes (26). PAI-1 production
was significantly correlated with that of TNF-a,
emphasizing a possible local contribution of TNF-a in the
obesity reviews Subcutaneous and visceral adipose tissue M. M. Ibrahim 13
© 2009 The Author
Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 11, 11–18
regulation of PAI-1 production by human adipose tissue
(28). Adiponectin has been shown to inhibit the TNF-ainduced
changes in monocyte adhesion molecule expression
and in the endothelial inflammatory response (29).
Interlukins and TNF-a are potent inhibitors of adiponectin
expression and secretion in human white adipose tissue
(30).
There are differences between VAT and SCAT regarding
the capacity to synthesize and release adipokines.
Leptin. Leptin expression and levels increase as the size of
adipose tissue TG stores increase (24,26). Subcutaneous fat
depot is the major source of leptin (7).
Adiponectin. Adiponectin is expressed more in VAT
than SCAT (5,31). There is significant negative correlation
between body weight and plasma adiponectin level.
Pro-inflammatory cytokines – TNF-a, CRP and IL-6. VAT
is more infiltrated with inflammatory cells and is more
capable of generating those proteins than SCAT (4,32,33).
Abdominal obesity increases levels of inflammatory
markers. CRP levels were significantly related to waist
circumference (WC) and VAT (34,35). Compared with
SCAT, VAT was more highly associated with monocyte
chemoattract protein-1 (35).
Angiotensinogen. Adipose tissue constitutes the most
important source of angiotensinogen after the liver (7).
Angiotensinogen is expressed more in VAT than SCAT
(36,37).
Plasminogen activator inhibitors-1. In obesity, PAI-1 levels
are increased. PAI-1 is expressed more in VAT than SCAT.
Omental adipose tissue secretes PAI-1 than does SCAT
(38).
Physiological and metabolic differences
Insulin resistance
Adipocytes from VAT are more insulin-resistant than SCAT
adipocytes (39,40). Smaller adipocytes tend to be more
insulin-sensitive; large adipocytes become insulin-resistant
(41,42). Amount of visceral fat is an important factor associated
with variations in insulin sensitivity (10,11,43).
Insulin resistance prevents glucose and more fat from
entering the cell and becoming preferentially oxidized. Subjects
with visceral abdominal obesity, when compared with
those with peripheral obesity, had lower glucose disposal,
glucose oxidation and greater lipid oxidation.
Insulin resistance may be one of the most important
factors linking abdominal visceral adiposity to cardiovascular
risk.
Rate of lipolysis – free fatty acids and
glycerol release
Visceral adipocytes are more metabolically active and have
a greater lipolytic activity than SCAT adipocytes (44,45).
VAT is more susceptible to the catecholamine-induced
lipolysis and less to the anti-lipolytic action of insulin.
Free fatty acids induce insulin resistance. In the liver,
insulin inhibits gluconeogenesis and glycogenlysis and
stimulates glycogen formation. Actions that limit hepatic
glucose production are shown in Fig. 1.
The degree of FFA suppression following meal ingestion
differs between abdominally and peripherally obese
persons. FFAs release is greater in the abdominally obese
individuals (5).
Glucose uptake
Visceral adipose tissue has higher rate of insulin-stimulated
glucose uptake compared with SCAT adipocytes.
Absorption of circulating free fatty acids
and triglycerides
Small adipocytes in SCAT have a high avidity for FFAs and
TG uptake. The new, small, more insulin-sensitive adipocytes
act as a sink or powerful ‘buffers’, avidly absorbing
circulating FFAs and TGs in the postprandial period (5,8).
SCAT cells may act as a buffer or sink for circulating FFAs
and TGs, but once they reach their capacity they loose their
protective benefit, fat begins to accumulate in tissues not
suited for lipid storage (5) (Fig. 2). SCAT in abdominal wall
has higher uptake of TGs and larger FFA release per kilograms
than does femoral fat (10,43).
Figure 1 Adverse effects of increased lipolysis and FFA mobilization.
FFAs, free fatty acids; TG, triglyceride.
14 Subcutaneous and visceral adipose tissue M. M. Ibrahim obesity reviews
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Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 11, 11–18
Clinical and prognostic differences
Metabolic risks
Visceral fat accumulation is associated with tendency to
hyperglycaemia, hyperinsulinemia, hypertriglyceridemia,
impaired glucose tolerance, increased apolipoproteins
B-rich lipoproteins, which are features of the insulin resistance
syndrome. Increased risk of developing diabetes is
greater in individuals with excess VAT (42,45,46). Individuals
with high levels of VAT area had higher mean
plasma cholesterol and TG levels and lower high-density
lipoprotein cholesterol values (47).
Metabolic syndrome
An increased body WC is considered now to be a prerequisite
of the metabolic syndrome.
Visceral obesity, like hyperinsulinemia and insulin resistance,
not only accompanies but antedates the components
of the metabolic syndrome (45,48).
Elevated arterial blood pressure that is one of the components
of the metabolic syndrome was explained by
insulin resistance and compensating hyperinsulinemia in
viscerally obese individuals (49–51). Central obesity can
induce the development of hypertension through increased
activity of adipose tissue renin-angiotensin-aldosterone
system, sympathetic activation and other mechanisms
closely connected with insulin resistance.
Vascular risk and cardiovascular events
Visceral fat quantified as waist size has been identified as an
independent risk factor for cardiovascular disease, hypertension
and stroke (46,52). Excess VAT has the potential to
cause hypercoagulability because of increased secretion of
PAI-1. Increased WC when accompanied by increased TG
leads to increased risk of coronary heart disease (53,54).
Abdominal obesity correlates closely with other measures
of atherosclerosis such as intima–media thickness
(55). Peripheral arterial disease also has been correlated to
VAT, but not to total body fat in elderly subjects (56).
Subjects with abdominal obesity were reported to have
greater risk of having an abnormal albumin excretion rate
(57). Microalbuminuria signifies enhanced cardiovascular
risk. Hyperinsulinemia, associated with visceral obesity, is
a predictor of coronary artery disease (58).
Increase in circulating FFAs in abdominal obesity is associated
with increase in cardiovascular risk. Elevations in
FFA levels promote endothelial dysfunction (50).
Assessment of cardiovascular risk in obese patients from
the measurement of body weight may be misleading (59).
Only obese individuals characterized by increased VAT
show the complications predictive of type 2 diabetes and
cardiovascular disease (51). Women generally display a
more favourable risk profile than men, and generally lower
level of VAT than men. Adjustments for differences in visceral
fat between men and women eliminated most of the
sex differences in cardiovascular risk factors (60). Peripheral
or gluteofemoral fat distribution seems to be protective
against atherosclerosis (61–63).
Prediction of mortality
Obesity is associated with increased cardiovascular disease
mortality (64,65). Cardiovascular disease death rates are
directly related to body mass index in both men and
women. Obesity in adulthood is also associated with a
striking reduction in life expectancy (66). Abdominal adiposity
as measured by WC is a significant predictor of
mortality independently of body mass index (67). Visceral
fat is a strong, independent predictor of all-cause mortality
in men (68).
Effects of weight reduction
Visceral adipose tissue is more sensitive to weight reduction
than SCAT (percentage wise) (69). All forms of weight
loss affect visceral fat more than subcutaneous fat (70).
However, recently Hall and Hallgreen (71) using simple
allometric model predicts that increasing weight loss
attenuates the preferential loss of VAT vs. SCAT. They
concluded that greater weight loss will cause a greater
absolute reduction of VAT mass.
Obesity being a chronic low-grade inflammatory state is
associated with increased plasma levels of inflammatory
markers such CRP. A recent study shows that weight reduction
is associated with decrease in CRP level. For every 1 kg
of weight loss, CRP levels dip by 0.13 mg L-1
(72). Other
adipokines also change with weight loss. Extreme weight
reduction in obese individuals was associated with an
increase in plasma adiponectin concentrations (73).
Figure 2 Energy surplus results in accumulation of triglycerides in
adipocytes at subcutaneous adipose tissue, which acts as a metabolic
sink. When capacity of subcutaneous fat is exceeded or if it is
impaired, fat will accumulate in areas outside the subcutaneous
compartment.
obesity reviews Subcutaneous and visceral adipose tissue M. M. Ibrahim 15
© 2009 The Author
Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 11, 11–18
Future directions
Research is needed on the molecular and cellular mechanisms
and signals for adipose tissue. Determination as to
which adipocyte factors are most important in promoting
metabolic disease will be an important focus for future
studies.
Manipulation of adipocyte biology might be a useful
therapeutic strategy in metabolic disease. There is a lot of
work that remains to be done in the area of adopocytes and
adipokines physiology. There are large gaps in our knowledge
about the mechanism of action of many adipokines.
The existence of additional, yet-unidentified adipocytespecific
factors is highly likely. Prospective cohort trials that
use imaging procedures to estimate abdominal and various
adipose tissue depots in a precise manner, assess biochemical
and metabolic parameters in relation to cardiovascular
endpoints are needed.
Racial differences in the accumulation of adipose tissue
depots and resulting cardiovascular risk need further
investigation.
Abdominal obesity is very common in Middle Eastern
countries (74). Women in Egypt and Turkey have the highest
proportion of overweight as well as the highest proportion
of obesity (75). Ongoing studies are aiming to identify the
WC cut-off points that define the threshold of abdominal
obesity and an abdominal waist girth. There are racial and
genetic variations in body fat distribution that dictates the
needs for different thresholds of abdominal obesity among
different populations. We are currently correlating in a
cross-sectional study (MM Ibrahim et al. unpublished
observations) the prevalence of a number of cardiovascular
risk factors at different levels of WC. The cut-off point based
upon this approach is different from the threshold among
US, European and Asian men and women.
Conflict of Interest Statement
No conflict of interest was declared.
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