The Critical Role of Intra-Abdominal Adiposity in Cardiometabolic Risk

FOCUS Cardiometabolic Risk, August 2007, Volume 1, Issue 1

Accumulating epidemiological, biological, and mechanistic evidence has shown that adipose tissue is an active endocrine and metabolic organ that plays a critical role in the development of cardiometabolic risk factors, diabetes, and cardiovascular disease.

Accumulating epidemiological, biological, and mechanistic evidence has shown that adipose tissue is an active endocrine and

metabolic organ that plays a critical role in the development of cardiometabolic risk factors, diabetes, and cardiovascular

disease. Adipose tissue and visceral

adipose tissue are sources of free fatty

acids and secrete a variety of biologically

active factors involved in the regulation of

lipid and glucose metabolism and energy

homeostasis. Excess intra-abdominal

adiposity contributes to the development

of multiple cardiometabolic risk factors

through increased flux of free fatty acids

in the portal circulation and dysregulation

of multiple adipocytokines that contribute

to altered energy metabolism and a

proinflammatory state. These cytokines

include adiponectin, leptin, interleukin-6,

tumor necrosis factor-alpha, and plasminogen

activator-1. Macrophage accumulation in

adipose tissue also promotes obesityassociated

inflammation and its sequelae,

including endothelial dysfunction, insulin

resistance, dyslipidemia, hypertension,

diabetes, and atherosclerosis. Rapidly

advancing scientific research is elucidating

novel pathways and physiologic systems

that regulate energy balance and intraabdominal

adiposity.

KEY POINT: Intra-abdominal adiposity is

now known to be an important contributor

to the development of cardiovascular

disease and diabetes. Adipose

tissue is a highly active endocrine organ

that secretes factors that regulate lipid

and glucose metabolism and energy

homeostasis. Excess visceral adiposity

contributes to the pathophysiology of

insulin resistance, hyperglycemia, dyslipidemia,

hypertension, and prothrombotic

and proinflammatory states. Thus,

the issues of excess intra-abdominal

adiposity go beyond the cosmetic.

Obesity is a problem of epidemic proportions

in the United States, with nearly

two thirds of American adults overweight

or obese.1 Along with upward trends

in general obesity, more and more

Americans have become abdominally

obese, with excess weight located in the

midsection. This is evidenced by National

Health and Nutrition Examination Survey

(NHANES) data showing that the ageadjusted

mean waist circumference

increased 3.0 cm in men and 3.2 cm in

women between the NHANES surveys of

1988-1994 and 1999-2000. During the

same interval, the age-adjusted prevalence

of high waist circumference (>102

cm in men and >88 cm in women) in

the United States increased from 29.5%

to 36.9% in men and from 46.7% to

55.1% in women.2 This high prevalence

of intra-abdominal adiposity is now under

increasing scrutiny as a contributor to

the development of cardiometabolic risk,

which includes cardiovascular disease

(CVD) and type 2 diabetes mellitus

(T2DM).

Adipose tissue, once considered an

inert depot for fat, is now known to be

a highly active metabolic and endocrine organ.3,4 Adipose tissue is an active

source of free fatty acids and secretes

a variety of cytokines, called adipocytokines,

that play key roles in the

regulation of lipoprotein and glucose

metabolism and energy homeostasis.

Adipocytokines include leptin, adiponectin,

tumor necrosis factor (TNF)-alpha,

interleukin (IL)-6, and plasminogen activator

inhibitor (PAI)-1.3,4 TNF-alpha and

IL-6 inhibit insulin receptor signaling and

block insulin action.4 Interestingly, this

effect of TNF-alpha on insulin signaling

is counterbalanced by another adipocytokine,

adiponectin.5

When visceral adipose tissue accumulates

in excess, it contributes to the

pathophysiology of multiple cardiometabolic

risk factors, including insulin

resistance, hyperglycemia, dyslipidemia,

hypertension, and prothrombotic and proinflammatory

states.4,6,7 Visceral adiposity

is a significant independent predictor

of insulin sensitivity,8-12 impaired glucose

tolerance,13 elevated blood pressure,14-16

and dyslipidemia.10,17-24

Overview of

Abdominal Fat Depots

Abdominal fat contains several discrete

anatomic depots: subcutaneous fat can

be categorized into either anterior and

posterior or superficial and deep; intraabdominal

fat includes both intraperitoneal

and retroperitoneal (or extraperitoneal)

sites. Intraperitoneal fat, often called

visceral fat, is composed of mesenteric

and omental fat masses. Although the

absolute volume of each of these depots

is much larger in upper-body obese than

in lean persons, the relative amount of

abdominal fat with respect to total body

mass is often similar in both groups.25

The nomenclature and anatomy of

abdominal fat depots are illustrated in

Figure 1.

The relative size of adipose tissue compartments

has been reported in a body

composition study by Chowdhury et al.26

Computed tomography imaging was

used in eight healthy males to measure

compartment sizes at the tissue and

organ levels. The study subjects were

aged 21-42 years with body-mass indices

(BMIs) ranging from 18.6 to 25.3

kg/m2; four subjects were of Indian

origin and four were Swedes. Results

showed that the distribution of adipose

tissue compartments was as follows:

true subcutaneous fat, 66.8%; visceral

fat, 20.7%; subcutaneous intramuscular

fat, 12.2%; and 0.3%, subcutaneous

extraperitoneal triangular fat pad.26

KEY POINT: Intra-abdominal fat volume

varies among ethnic populations.

African Americans appear to have

less visceral fat than Caucasians and

Hispanics, and Asians and Japanese

have more visceral fat than Caucasians.

It should be recognized that there are

ethnic differences in abdominal visceral

fat volume. The literature suggests that

African Americans have less abdominal

visceral fat than Caucasians and

Hispanics, and Asians and Japanese

have more abdominal visceral fat than

Caucasians. Various studies have

reported that visceral adipose tissue

volume is lower in African American

women27-31 and men30 vs white women

and men. In a cohort from the Insulin

Resistance Atherosclerosis Study (IRAS),

Wagenknecht et al11 reported that

Hispanics had higher visceral adipose

tissue volume than African Americans

for similar or lower BMI. Tanaka et al32

reported that Japanese had a greater

amount of abdominal visceral fat relative

to abdominal subcutaneous fat than

Caucasians, confirming a similar finding

in Asian American women by Park et al.33

Visceral fat secretes higher levels of

certain adipokines than does subcutaneous

adipose tissue, including interleukin

(IL)-6 (a potent inflammatory cytokine),

vascular endothelial growth factor (an

important protein involved in angiogenesis),

and plasminogen activator inhibitor

(PAI)-1 (the primary inhibitor of fibrinolysis).

34-36 Products released from visceral

adipose tissue travel directly to the liver

via the portal circulation,so individuals

with excess intra-abdominal adiposity

may be inundating their livers with

inflammatory cytokines and excess free

fatty acids.

Intra-Abdominal

Adiposity: Link to

Cardiometabolic Risk

In recent years, accumulating evidence

has demonstrated higher cardiovascular

and metabolic risk associated with

intra-abdominal adiposity compared

with general obesity. Visceral adipose

tissue, deposited in the intra-abdominal

region, predicts health risks associated with obesity (Figure 2 and Table 1).

Epidemiological studies have shown that

high waist circumference, an easily identifiable

marker for intraabdominal adiposity,

increases this risk of CVD and T2DM.

Intra-Abdominal Adiposity

as a Predictor of

Cardiovascular Disease

KEY POINT: Longitudinal studies demonstrate

that increased waist circumference,

an easily identifiable marker for

intra-abdominal adiposity, elevates the

risk of CVD.

Dagenais et al39 demonstrated that the

risk of cardiovascular death, myocardial

infarction (MI), and all-cause death

increased in parallel with an increasing

waist circumference in a study of 6,620

men and 2,182 women with stable CVD

but no congestive heart failure participating

in the Heart Outcomes Prevention

Evaluation (HOPE) trial. The authors

concluded that obesity, particularly intraabdominal

adiposity, worsens the prognosis

of patients with CVD, as shown in

Figure 3 (on the next page).

In the female-cohort Nurses’ Health

Study, Rexrode et al40 found that high

waist circumference was associated

with an increased risk of coronary heart

disease (CHD). Responses from 44,702

women aged 40 to 65 years who were

free of CHD, stroke, and cancer as of

1986 were analyzed, with follow-up in

1994. The primary outcome was the

incidence of CHD, defined as nonfatal MI

or CHD death. During the 8-year evaluation

period, there were 320 CHD events.

After adjustment for BMI and existing

cardiac risk factors, high waist circumference

was found to be independently

associated with increased relative risk of

CHD in women with BMI ≤25 kg/m2. As

shown in Figure 4 (on the next page), a

woman with a waist circumference of 30

to 32 inches had a twofold higher risk of

CHD, compared with a normal waist circumference

of <28 inches. Women in the

highest waist-circumference range (35 to

56 inches) had a relative risk of 2.44,40

Measures of intra-abdominal adiposity

are predictive of CVD, as reported by

Dagenais and Rexrode; studies also suggested

that waist circumference is a

better prognostic indicator of CVD than

overall obesity as measured by BMI.41

Lakka and colleagues analyzed CVD

outcomes in 1,346 Finnish men with

no history of CVD at baseline. BMI was

measured as an indicator of overall obesity,

while waist-hip ratio and waist circumference

were measured as indicators

of abdominal obesity. Average follow-up

time was 10.6 years, with a total of 123

coronary events being documented. Men

in the three higher quartiles of waisthip

ratio had nearly a threefold greater

risk of coronary events than men in the

lowest quartile. Men in the two highest

quartiles of waist circumference had

an approximate twofold risk of events

compared with those in the lowest two

quartiles, demonstrating a significant

linear correlation between waist circumference

and number of events. BMI was less consistently associated with CVD

risk than either waist-hip ratio or waist

circumference.41

Further evidence for the role of intraabdominal

adiposity as a key predictor

of CVD comes from the landmark

INTERHEART study.42 INTERHEART was

the first large, international study to

establish that obesity is a cardiovascular

risk factor that is statistically significant

across the world’s populations. All

patients admitted to the coronary care

unit or equivalent cardiology ward were

screened for a first MI at 262 participating

centers in 52 countries throughout

Africa, Asia, Australia, Europe, the

Middle East, and North and South

America. Study results identified nine

potentially modifiable risk factors that

affected men and women of different

ethnic groups consistently, including

smoking, hypertension, diabetes, lack

of physical activity, low intake of fruits

and vegetables, and abdominal obesity.

Combined, these risk factors accounted

for >90% of the risk of an initial acute

MI, indicating the importance of a

healthy lifestyle in reducing the risk

of CVD. In a subsequent prespecified

analysis of INTERHEART, it was determined

that waist circumference was

a more powerful predictor of obesityassociated

CVD risk level than any other

single measure of obesity (eg, BMI) or

constellation of measures (eg, metabolic

syndrome).

Taken together, the above studies suggest

that intra-abdominal adiposity is a

potent identifier of future cardiometabolic

risk leading to CVD, and that high waist

circumference is a predictive measure of

central obesity.

Intra-Abdominal Adiposity

as a Predictor of Type 2

Diabetes Mellitus

KEY POINT: Longitudinal studies demonstrate

that increased waist circumference,

a marker for intra-abdominal adiposity,

elevates the risk of T2DM.

In addition to its association with CVD,

high waist circumference has also been

shown in epidemiological studies to be

a predictor of T2DM. In a female cohort

from the Nurses’ Health Study, Carey et

al43 reported that high waist circumference

was associated with increased

risk of T2DM. Among 43,581 women

who in 1986 provided waist, hip, and

weight measurements and who were free

from diabetes and other major chronic

illnesses, the incidence of T2DM was

followed from 1986 to 1994. Results

showed a strong positive association

between waist circumference and the

incidence of diabetes, as shown in Figure

5. Women with a waist circumference

≥38 inches had a diabetes risk of 22.4,

relative to women with a normal waist

circumference (<28 inches). Other obesity

measures studied included BMI and

waist-to-hip ratio; both of these were also

found to be independent determinants of

T2DM in this population. The sharpest

risk gradient was documented with waist

circumference, indicating that it is a

powerful independent predictor of T2DM

in women.

In the prospective male-cohort Health

Professionals Follow-up Study, Wang et

al44 evaluated BMI, waist-hip ratio, and

waist circumference as predictors of

T2DM in 27,270 participants. As Figure

6 (on the next page) illustrates, all three

measures strongly and independently predicted the risk of T2DM. Of note,

intra-abdominal adiposity as measured by

waist circumference was a better predictor

than was waist-hip ratio or BMI.

These epidemiological and biochemical

data demonstrate the clear role

that intra-abdominal adiposity plays in

elevating cardiometabolic risk leading to

T2DM.

Association of Intra-

Abdominal Adiposity With

Cardiometabolic Risk

Factors

KEY POINT: Intra-abdominal adiposity is

associated with multiple cardiometabolic

risk factors.

In light of the overall association of intraabdominal

adiposity with CVD and T2DM,

it is not surprising that visceral fat has

also been shown to be independently

associated with cardiometabolic risk factors.

Visceral adipose tissue is associated

with dyslipidemia, insulin resistance,

elevated blood glucose, hypertension,

and prothrombotic and proinflammatory

states,4 as depicted in Figure 7.

In a large study of healthy men and

women, Carr et al24 evaluated the differential

effects of body fat distribution

and insulin sensitivity on the features of

the metabolic syndrome (defined by Adult

Treatment Panel III criteria: blood pressure

≥130/85 mm Hg, waist circumference

>102 cm in men and >88 cm in women,

high-density lipoprotein cholesterol [HDLC]

<40 mg/dL in men and <50 mg/dL in

women, triglycerides >150 mg/dL, and

fasting plasma glucose ≥110 mg/dL).

Results showed that both intra-abdominal

adiposity and insulin resistance were

significant correlates of the metabolic syndrome.

However, intra-abdominal fat area

was independently associated with all five

components of the metabolic syndrome,

while insulin sensitivity was independently

associated with only three components

(HDL-C, triglycerides, and fasting plasma

glucose). Of note, abdominal subcutaneous

fat area was independently correlated

with only one of the metabolic syndrome

components (waist circumference) after

adjusting for intra-abdominal fat area and

insulin sensitivity.

Various studies have shown that intraabdominal

adiposity, but not abdominal

subcutaneous fat, is independently

associated with insulin resistance,18

lower HDL-C,18,19 higher apolipoprotein

B18,19 and triglyceride levels,18,19

smaller low-density lipoprotein (LDL)

particles,22 aortic stiffness,45 coronary

artery calcification,46 and higher blood

pressure.14-16 These associations of

increased intra-abdominal fat with a

more atherogenic lipoprotein profile

have been reported by various investigators

using different data analyses, as

summarized in Table 2.

Evidence suggests that individuals with

metabolic syndrome who have visceral fat

accumulation as an underlying pathology have more severe insulin resistance

and a higher risk of arteriosclerosis, as

compared to individuals with metabolic

syndrome without visceral fat accumulation.

47 Further suggesting a pathophysiological

role for visceral fat accumulation

in cardiometabolic risk, Salmenniemi et

al48 demonstrated for the first time that

insulin resistance in people with the

metabolic syndrome is seen not only in

skeletal muscle but also in adipose tissue,

leading to

multiple defects in glucose and energy

metabolism, hypoadiponectinemia,

and elevated levels of proinflammatory

cytokines and adhesion molecules. The

biochemical rationale for a causative

pathophysiologic role of intra-abdominal

adiposity in cardiometabolic risk is discussed

in the next section.

Adipose Tissue as an

Endocrine Organ:

Evidence for a

Contributing Role in

Cardiometabolic Risk

KEY POINT: In excess, visceral fat is

considered to be a high-risk fat.

Intra-abdominal adipose tissue is a

highly active metabolic and endocrine

organ, expressing cytokines that play

a significant regulatory role in lipid

and glucose metabolism and energy

homeostasis.

The precise mechanism behind the

increased cardiometabolic risk from

abdominal adiposity vs subcutaneous

adiposity is not known, but numerous

studies support a role for abdominal fat.

The link to insulin resistance is partly

explained by the increased levels of

free fatty acids that typically accompany

excess abdominal adiposity.49 Visceral

fat is connected by the portal venous

system to the liver, allowing direct flux

of free fatty acids into the liver. It is suggested

that elevated levels of free fatty

acids inhibit the insulin-signaling mechanism,

which causes decreased glucose

transport to skeletal muscle. Free

fatty acids also play a mediating role

between insulin resistance and beta-cell

dysfunction.49 Abdominal obesity is also

associated with decreased levels of

adiponectin, the hormone expressed by

adipocytes, which also contributes to

insulin resistance.50 Elevated C-reactive

protein (CRP) is believed to be triggered

by excess abdominal adiposity; it is

indicative of inflammation in the body

and has been shown to be predictive

of CVD and insulin resistance.7 Obesity

has been shown to be associated with

the inflammation cascade, with macrophages

contained in adipose tissue

expressing a number of inflammatory

cytokines.

It is now clear that adipose tissue is a

complex and highly active metabolic

and endocrine organ.3,4 Adipose tissue

expresses and secretes diverse bioactive

factors (Table 3), including cytokines,

inflammatory mediators, fatty

acids, and adipokines such as leptin and

adiponectin, and most of these act at

both the local (autocrine/paracrine) and

systemic (endocrine) levels. In addition

to efferent signals, adipose tissue also

expresses various receptors that allow

it to respond to afferent signals from

traditional hormone systems as well as

from the central nervous system (eg,

insulin, glucagon, glucagon-like peptide

1, glucocorticoids, thyroid hormone,

and catecholamines).4 Adipose tissue

contains the metabolic mechanisms to

allow crosstalk with distant organs and

is integrally involved in coordinating a

variety of biological processes, including

energy metabolism (Figure 8) and neuroendocrine

function.

The composition of adipose tissue and its role as a complex, hyperkinetic

endocrine organ offer insight into the

pathogenesis of cardiometabolic risk.

It is composed of adipocytes, a connective

tissue matrix, nerve tissue,

stromovascular cells, and immune

cells.4 Many of the proteins secreted

by adipose tissue act as a metabolic

signaling mechanism, interacting with

the central nervous system and organs

throughout the body.4 Characteristics

and effects of specific adipocytokines—

including adiponectin, leptin, IL-

6, TNF-alpha, and PAI-1—are described

in the next sections.

Adiponectin

KEY POINT: Adiponectin is an adipocyte-

derived hormone that has antidiabetic,

antiinflammatory, and antiatherogenic

properties. Metabolic

effects of adiponectin have been

observed in the liver, muscle, vascular

wall, and endothelial cells.

Adiponectin levels are reduced in the

setting of obesity, particularly with

intra-abdominal fat accumulation.

One of the adipocytokines that appears

to be strongly associated with cardiometabolic

risk is adiponectin.

Adiponectin plays a key role in the regulation

of fat and glucose metabolism.50

This adipocyte-derived hormone has

insulin-sensitizing and antiatherogenic

properties. Adiponectin replenishment

has ameliorated insulin resistance in

insulin resistant mice,53 reduced atherosclerosis

in apolipoprotein-E—deficient

mice,54 and improved hypertension in

adiponectin-knockout mice.55 In humans,

clinical studies have demonstrated that

decreased adiponectin concentrations

are associated with the presence of

T2DM and CVD.56,57

Adiponectin is highly expressed in differentiated

adipocytes and circulates at

high levels in the bloodstream.58 Two

adiponectin receptors have been identified—

AdipoR1, expressed primarily in

muscle, and AdipoR2, expressed primarily

in liver.59 The biological effects of adiponectin

depend on not only the relative

circulating concentrations and properties

of the different adiponectin isoforms (eg,

full-length and globular), but also the tissue-

specific expression of the adiponectin

receptor subtypes.4

Several mechanisms for adiponectin’s

metabolic effects have been observed

in different tissues.4 In the liver, adiponectin

enhances insulin sensitivity,

decreases influx of nonesterified fatty

acids, increases fatty acid oxidation,

and reduces hepatic glucose output. In

muscle, adiponectin stimulates glucose

use and fatty acid oxidation. Within

the vascular wall, adiponectin inhibits

monocyte adhesion by decreasing adhesion-

molecule expression, inhibits macrophage

transformation to foam cells

by inhibiting expression of scavenger

receptors, and decreases proliferation

of migrating smooth muscle cells in

response to growth factors. Adiponectin

also increases nitric oxide production in

endothelial cells and stimulates angiogenesis.

These effects are mediated by

increased phosphorylation of the insulin

receptor, activation of AM-Pactivated

protein kinase, and modulation of the

nuclear factor kappa-B pathway.58,60

These data demonstrate that adiponectin

is a unique adipocyte-derived hormone

with antidiabetic, anti-inflammatory,

and antiatherogenic effects.4

Plasma adiponectin levels are reduced

in insulin-resistant states, including

obesity, T2DM, CVD, hypertension, and

metabolic syndrome.61 Xydakis and colleagues

evaluated the relationship of

adiponectin with inflammation, adiposity,

and insulin resistance in 40 subjects

with metabolic syndrome, compared

with 40 subjects without metabolic

syndrome.62 Adiponectin levels were

significantly lower in patients with metabolic

syndrome than in those without.

As illustrated in Figure 9, adiponectin

levels decreased and TNF-alpha levels

increased with the number of metabolic

syndrome factors present (high triglycerides,

low HDL-C, elevated blood pressure,

elevated blood glucose, and high

waist circumference).62

Genetic mutation studies of adiponectin

in humans and knockout mice demonstrate

that adiponectin may play a

key role in the prevention of metabolic

syndrome.4,5,54,63-67 Hypoadiponectinemia

together with the increase of TNF-alpha

or PAI-1 induced by the accumulation of

visceral obesity might be a major background

of vascular changes and metabolic

disorders that are characteristic of

the metabolic syndrome.67

Decreased plasma adiponectin levels

have been strongly associated with

insulin resistance, while increased

levels have been associated with

improved insulin sensitivity. In a study

of obese Japanese subjects with

T2DM and CVD, two conditions commonly

associated with insulin resistance

and hyperinsulinemia, plasma

levels of adiponectin were found to

be decreased.68 Conversely, increased

adiponectin levels have been determined

to be associated with improved

insulin sensitivity.58 Studying the relationships

between adiponectin, body

fat distribution, insulin sensitivity, and

lipoproteins, Cnop et al69 demonstrated

that adiponectin potentially links

intra-abdominal fat with insulin resistance

and an atherogenic lipid profile.

Simple regression analysis showed

that adiponectin was positively correlated

with age and insulin sensitivity,

and negatively correlated with BMI

and subcutaneous and intra-abdominal

fat. Adiponectin was negatively correlated

with triglycerides and positively

correlated with HDL-C and LDL

particle buoyancy. Multiple regression

analysis showed that adiponectin was

related to age, gender, and intraabdominal

fat. Insulin sensitivity was

related to intra-abdominal fat and adiponectin.

Both intra-abdominal fat and

adiponectin contributed independently

to triglycerides, HDL-C, and LDL-C

particle buoyancy. The data suggest

that adiponectin concentrations are

determined in part by intra-abdominal

fat mass.

Leptin

KEY POINT: Leptin, a metabolic signal of

energy sufficiency, is secreted by adipocytes

in proportion to adipose tissue

volume and nutritional status. It exerts

multiple effects on energy homeostasis

through hypothalamic pathways and

peripheral pathways in the muscle and

pancreas. Obesity is often accompanied

by increased leptin levels and by

leptin resistance. Since leptin provides

feedback of energy sufficiency to central

appetite regulating mechanisms,

low levels can result in increased

appetite and decreased energy expenditure,

leading to weight gain.

Leptin is a circulating endocrine hormone

that communicates the status of

energy stores from the periphery to the

central nervous system; it is a metabolic

signal of energy sufficiency rather

than excess.4,70 Leptin is secreted by

adipocytes proportionally to adipose

tissue volume and nutritional status,

though its expression and secretion

are also regulated by other factors.4,71

Insulin, glucocorticoids, TNF-alpha,

and estrogens increase leptin; beta-

3—adrenergic activity, androgens,

free fatty acids, growth hormone, and

peroxisome proliferator-activated receptor

(PPAR)-gamma agonists decrease

leptin.4,72

Leptin exerts multiple effects on energy

homeostasis.73 Hypothalamic pathways

mediate many of these effects, especially

energy intake and expenditure,

and other effects are mediated peripherally

through direct action in muscle

and pancreatic beta-cells.74 Calorie

restriction and weight loss reduce leptin

levels, and this reduction is associated

with increased appetite and decreased

energy expenditure. The same responses

are observed in leptin-deficient mice

and humans, despite massive obesity,

and the responses are normalized by

leptin replacement. Conversely, common

forms of obesity are characterized by

elevated circulating leptin and also by

leptin resistance. Neither endogenously

high leptin levels nor exogenously

administered leptin are effective in

reducing this obesity.74,75 The concept

that leptin is an indicator of energy sufficiency

but not excess emanates from

its dose-response curve. Low leptin levels

are induced by food restriction, rising

levels are induced by refeeding, and

supraphysiological levels are observed

in obesity.4

Besides its significant role in energy

homeostasis, leptin also regulates

neuroendocrine function and traditional endocrine systems, including the hypothalamic-

pituitary-adrenal (HPA) axis and

the hypothalamicpituitary-thyroid and

-gonadal axes.72,74,76-78

Interleukin-6

KEY POINT: IL-6 is a proinflammatory

adipocytokine involved in insulin and

leptin signaling, adipogenesis, and

adiponectin secretion. One third of

circulating IL-6 derives from adipose

tissue, predominantly from visceral

fat. IL-6 modulates production and

release of the inflammatory factor

CRP from the liver.

IL-6 is a proinflammatory adipocytokine

implicated in the pathogenesis of

obesity, insulin resistance, and CVD.

IL-6 expression and plasma levels

increase in proportion to adiposity

and as a result of changes in energy

balance.3 Expression and secretion of

IL-6 are two- to threefold higher in visceral

vs subcutaneous fat.34,36,71 IL-6

circulates at high levels in the bloodstream,

and as much as one third of

circulating IL-6 derives from adipose

tissue.79 This is of interest because

IL-6 modulates proinflammatory CRP

production in the liver.80 Excess adipose

tissue appears to elevate the

circulating levels of IL-6 and, consequently,

the levels of circulating CRP.

CRP is the inflammatory marker most

commonly associated with IL-6. It is

also commonly associated with insulin

resistance, atherosclerosis, and

cardiovascular risk. CRP is thought to

directly participate in the endothelial

cell mechanisms that lead to atherosclerotic

lesions and cardiac events.81

A growing body of evidence demonstrates

that CRP levels predict the

occurrence of CVD and T2DM.

IL-6 exerts multiple peripheral effects,

including decreased insulin and leptin

signaling in peripheral tissues,82

inhibition of adipogenesis, and

decreased adiponectin secretion.79

These detrimental peripheral effects

are consistent with epidemiological

findings that suggest a causal role for

IL-6 in obesity and insulin resistance.4

For example, the expression and circulating

levels of IL-6 increase with

obesity, impaired glucose tolerance,

and insulin resistance, and decrease

with weight loss. Plasma IL-6 concentrations

are also predictors of T2DM

and CVD.79

Tumor Necrosis

Factor-Alpha

KEY POINT: The proinflammatory adipocytokine

TNF-alpha plays a role in the

pathophysiology of obesity and insulin

resistance. Metabolic actions of TNFalpha

inhibit glucose uptake and fatty

acid oxidation, increase expression of

genes involved in de novo synthesis of

cholesterol and fatty acids, and impair

insulin signaling.

Like IL-6, TNF-alpha is a proinflammatory

adipocytokine implicated in the

development of obesity and insulin

resistance.4 TNF-alpha increases in

proportion to adiposity and as a result

of changes in energy balance.3,83

Plasma levels of TNF-alpha have been

shown to increase in the presence of

the metabolic syndrome (see Figure 9

on page 15).62

In adipose tissue, TNF-alpha represses

genes involved in the uptake and

storage of nonesterified fatty acids

and glucose, suppresses genes for

transcription factors involved in adipogenesis

and lipogenesis, and changes

the expression of adiponectin and IL-

6.84 In the liver, TNF-alpha suppresses

expression of genes involved in

glucose uptake and metabolism and

fatty acid oxidation; it also increases

expression of genes involved in de

novo synthesis of cholesterol and

fatty acids. TNF-alpha impairs insulin

signaling directly by activation of serine

kinases, and indirectly by increasing

serum nonesterified fatty acids,

which can induce insulin resistance in

multiple tissues.4,85

Plasminogen Activator

Inhibitor-1

KEY POINT: PAI-1 is an adipocytesecreted

protein that is the primary

inhibitor of fibrinolysis. Its expression

and secretion are greater in visceral

fat than in subcutaneous fat. PAI-1

levels are elevated in obesity and

insulin resistance and predict future

cardiometabolic risk leading to T2DM

and CVD.

PAI-1 is an adipocyte-secreted protein

of the hemostasis and fibrinolytic

system and is a member of the serine

protease inhibitor family.4 PAI-1 is the

primary inhibitor of fibrinolysis (by

inactivating urokinase-type and tissuetype

plasminogen activator86) and has

been implicated in angiogenesis and

atherogenesis. PAI-1 is expressed by

many cell types within adipose tissue,

including adipocytes, and its expression

and secretion are greater in visceral

vs subcutaneous fat.34

Plasma PAI-1 levels are elevated in

obesity and insulin resistance, are

positively correlated with features of

the metabolic syndrome, and predict

future risk of T2DM and CVD.86,87

Plasma PAI-1 levels are strongly

associated with visceral adiposity,

independent of insulin sensitivity, total

adipose tissue mass, or age.71,86

Interestingly, evidence suggests that

PAI-1 contributes to the development

of obesity and insulin resistance and

may be a causal link between obesity

and CVD.4 Weight loss and improvement

in insulin sensitivity due to

pharmacotherapy significantly reduce

circulating PAI-1 levels.86 Targeted

deletion of PAI-1 in mouse models

has been associated with decreased

weight gain on high-fat diet, increased

energy expenditure, improved glucose

tolerance, enhanced insulin sensitivity,

decreased adiposity, and improved

metabolic parameters.88,89

The Endocannabinoid

System, Adipose Tissue,

and Energy Metabolism

KEY POINT: The endocannabinoid system

(ECS) is an endogenous signaling system

that plays a role in the regulation

of energy homeostasis and lipid and

glucose metabolism. Increased activity

of the ECS is strongly associated

with obesity and dyslipidemia. The ECS

appears to be a promising novel mechanistic

pathway that modulates

important aspects of the development

of cardiometabolic factors through

peripheral pathways involving adipocytes

and adipocytokines such as

adiponectin as well as through central

regulatory pathways.

The ECS is a recently characterized

physiologic system that plays an important

role in the regulation of energy

metabolism—in part through peripheral

pathways that involve adipocytes and

adipocytokines such as adiponectin.

An endogenous signaling system, the

ECS consists of two types of receptors

that have been characterized,

CB1 and CB2, and several endogenous

ligands, of which anandamide and 2-

arachidonylgycerol have been the most

studied. These endogenous ligands, or

endocannabinoids, are not preformed

and stored in cells prior to use. Rather,

when endocannabinoids are needed, the

enzymes that synthesize them are rapidly

activated. Endocannabinoids act locally

as retrograde messengers in the nervous

system. After their release from postsynaptic

cells, they bind to and activate

CB1 receptors located presynaptically.

Thereafter, they are rapidly inactivated,

and this is thought to be mediated

through reuptake by a transport protein.

In non-neural cells, such as adipose tissue,

the ECS appears to have additional,

possibly longer-term modulatory effects

by influencing gene transcription of certain

proteins such as adiponectin.

Physiologically, the ECS plays a role

in modulating energy balance, feeding

behavior, hepatic lipogenesis, and glucose

homeostasis (Figure 10). Evidence

suggests that the ECS has a chronic

increase in activity in human obesity

and in animal models of genetic and

diet-induced obesity. ECS stimulation

centrally and peripherally favors metabolic

processes that lead to weight

gain, lipogenesis, insulin resistance,

dyslipidemia, and impaired glucose

homeostasis.

In the brain, the overall effect of endocannabinoids

acting at both hypothalamic91

and brainstem sites92 is to place

the body in a state of net energy gain.93

In peripheral pathways, as part of the

ECS function to promote anabolism,93

CB1 receptors are found in metabolically

active tissues such as fat cells and the

liver. Adipocytes express CB1 receptors;

activation of these receptors can induce

lipogenesis by increasing adipose-tissue

lipoprotein lipase expression91 and

antagonism of these receptors increases

adiponectin gene expression.94 CB1

receptor stimulation has been shown to

reduce the expression of AMP-activated

protein kinase (AMPK) in visceral fat.95

AMPK is an enzyme that functions as a

fuel sensor to regulate energy balance

pathways, including fat oxidation and

glucose transport, at both cellular and

whole-body levels.

Matias et al96 extended the findings

that the ECS and adipose tissue play

a direct role in the peripheral control

of energy homeostasis. Their analysis

of animal and human adipocytes, beta

cells, serum, and adipose tissue samples

demonstrated that endocannabinoid-

CB1 signaling participates in adipocyte

differentiation and lipid accumulation,

and remains activated in mature

adipocytes, where it reduces adiponectin

expression. Endocannabinoid-CB1

signaling was also shown to be overactive

in the adipose tissue and pancreas of mice with diet-induced obesity (a

condition similar to human obesity) and

in the visceral adipose tissue of obese

patients.

A summary of evidence of the ECS as a

regulator of energy metabolism in adipocytes

appears in Table 4 (on page 17).

Adipose Tissue

and Inflammation:

Evidence for a

Contributing Role in

Cardiometabolic Risk

KEY POINT: The enlarged adipocytes of

obese individuals recruit macrophages,

promote inflammation, and release a

range of factors that predispose toward

insulin resistance. Together, adipocytes

and macrophages interact, increasing circulating

proinflammatory cytokines, promoting

a chronic, systemic inflammatory

response that adversely affects metabolic

function and leads to atherosclerosis.

A number of inflammatory mediators are

implicated in the pathogenesis of obesity

and the mechanisms responsible

for the development of chronic diseases

associated with obesity, such as CVD

and T2DM. As discussed in the previous

section, adipose tissue releases

hormones that modulate body fat mass.

As a person gets heavier and adipocytes

enlarge, these control mechanisms

become dysregulated, macrophages

accumulate in adipose tissue, and

inflammation ensues.100 Compared with

lean individuals, adipose tissue in obese

persons shows higher expression of

inflammatory and prothrombotic proteins

(eg, TNF-alpha, IL-6, and PAI-1).100

Excess visceral fat stimulates the

release of CRP from the liver. It also

expresses cytokines involved in the

white cell migration known to cause the

accumulation of macrophages in the

intima, a key factor in plaque formation.

An important concept is that fatdepleted

adipocytes in lean individuals

promote metabolic homeostasis; the

enlarged adipocytes of obese individuals

recruit macrophages and promote

inflammation and the release of a range

of factors that predispose toward insulin

resistance.100

Adipocytes, Macrophages,

and Inflammation

Obese adipose tissue is characterized by

inflammation and progressive infiltration

by macrophages as obesity develops.

Changes in adipocyte and fat pad size

lead to physical changes in the surrounding

area and modifications of the

paracrine function of the adipocyte. For

example, in obesity, adipocytes secrete

low levels of TNF-alpha, which can stimulate

preadipocytes to produce monocyte

chemoattractant protein-1 (MCP-1).

Similarly, endothelial cells also secrete

MCP-1 in response to cytokines. Thus,

either preadipocytes or endothelial cells

could be responsible for attracting macrophages

to adipose tissue. The early

timing of MCP-1 expression prior to that

of other macrophage markers during the

development of obesity suggests that it

is produced initially by cells other than

macrophages.101

Increased secretion of leptin, decreased

production of adiponectin, or both by

differentiated adipocytes (not preadipocytes)

may also contribute to further

macrophage accumulation by stimulating

transport of macrophages to adipose

tissue and promoting adhesion of macrophages

to endothelial cells, respectively.

Physical damage to the endothelium—

caused either by size changes and crowding

or oxidative damage resulting from

a lipolytic environment—may also play a

role in macrophage recruitment, similar

to that seen in atherosclerosis.101

Regardless of the initial stimulus to

recruit macrophages into adipose tissue,

once macrophages are present and

active, they could perpetuate a vicious

cycle of macrophage recruitment, production

of inflammatory cytokines, and

impairment of adipocyte function.101 This

process of macrophage recruitment and

accumulation in enlarged adipocytes is

depicted in Figure 11 and, along with its

impact on obesity-related sequelae, in

Figure 12 (on the next page).

Although adipocytes and macrophages

derive from different precursors and have

different physiological functions, there

appears to be a convergence of their

functions in obesity and the metabolic

syndrome. In the pathological setting of

obesity and insulin resistance, both cell

types engage in lipid storage and cytokine

secretion, as shown in Figure 13 (on

the next page).102 As mentioned above,

adipose tissue is infiltrated by macrophages

in the presence of obesity, insulin

resistance, or both.

Macrophages are responsible for most

of the cytokine production in obese

adipose tissue.103,104 Adipose tissue

macrophages are responsible for almost

all adipose tissue TNF-alpha expression and significant amounts of IL-6 expression.

103 Xu et al104 reported that the

increased expression of inflammationspecific

genes by macrophages in the

adipose tissue of obese mice preceded

a dramatic increase in insulin production.

When these mice were treated with

an insulin-sensitizing drug, expression of

these genes declined. Thus, the appearance

of these inflammatory molecules

before the development of insulin resistance,

as well as their known ability to

promote insulin resistance and other

complications of obesity, strongly suggests

that adipose tissue inflammation

plays an important role in the development

of obesity-related complications.100

Inflammation is thought to contribute

to the development of the sequelae of

obesity. Obesity decreases adiponectin

production,105 and adiponectin is an

inhibitor of TNF-alpha—induced monocyte

adhesion;106 this may be an important

link between obesity and

atherosclerosis.

Waist Circumference:

A Clinically Practical

Surrogate Marker for

Intra-Abdominal Fat

KEY POINT: While advanced imaging

techniques such as computed tomography

provide accurate assessment

of abdominal fat deposition, waist

circumference has been shown to be

a clinically practical and highly correlative

surrogate measure of visceral

adipose tissue. Waist circumference is

a better anthropometric correlate of

visceral fat than is waist-hip ratio.

BMI provides a measure of overall adiposity,

but the actual physiologic distribution of

excess adipose tissue may be the primary

factor in both elevating cardiometabolic

risk as well as predicting the associated

health risks. Waist circumference is a

highly correlative and easily performed

method for estimating intra-abdominal fat

and, in clinical practice, may be more valuable

than BMI for a number of reasons.2

• Epidemiologic studies show that

waist circumference is a strong predictor

of CVD, T2DM, and metabolic

syndrome, as discussed earlier in

this monograph.

• Waist circumference provides information

about health risks—such as

diabetes, hypertension, and dyslipidemias—

independent of BMI.107

• Waist circumference may be a better

predictor of medical care costs than

BMI.108

• Waist circumference is conceptually

easy to measure, and guidelines

have helped to standardize the proper

technique, as shown in Figure

14 (on the next page). Computed

tomography109 and magnetic resonance

imaging110 provide incremental

accuracy over office-based waist

circumference measurement, but

they are impractical for routine clinical

use.38

• Patients may find waist circumference

easier to understand and measure than

BMI, thereby providing opportunities for

patient self-identification.

• While some guidelines stipulate that

elevated waist circumference is simply

one of the criteria for the metabolic

syndrome,37,111,112 other guidelines (eg,

International Diabetes Federation [IDF])

require elevated waist circumference

as an essential component for the

diagnosis. Under the IDF criteria, diagnosis

of the metabolic syndrome can

only be made if central obesity is present

along with two or more risk factors

(raised triglycerides, reduced HDL-C,

raised blood pressure, and raised fasting

plasma glucose or T2DM).112

• Various other guidelines for obesity,

diabetes, and CVD—including the

National Heart, Lung, and Blood

Institute (NHLBI)/North American

Association for the Study of Obesity

(NAASO) guidelines in 1998 and

most recently the American Heart

Association/American College of

Cardiology secondary prevention

guidelines in 2006—recognize the

importance of measuring waist circumference

as an indicator of abdominal

adiposity and health risks.38,113

Sophisticated imaging techniques such

as magnetic resonance imaging and

computed tomography can distinguish,

with a high level of precision, intraabdominal

or visceral fat from subcutaneous

abdominal fat.109,110 These

techniques have shown that waist

circumference is a better anthropometric

correlate than waist-hip ratio of the

amount of visceral adipose tissue. The

close correlation of waist circumference

with visceral adipose tissue is shown in

Figure 15.115,116

Therapeutic

Approaches to

Intra-Abdominal

Adiposity

KEY POINT: Approaches to long-term

weight management include therapeutic

lifestyle changes, pharmacotherapy,

and surgery. Liposuction of abdominal

subcutaneous adipose tissue has been

shown not to improve cardiometabolic

risk factors, whereas experimental

studies report that reduction of visceral

fat improved glucose levels and

insulin sensitivity.

In overweight and obese individuals, there

is strong evidence that weight loss reduces

risk factors for CVD and T2DM. Weight

loss reduces blood pressure, improves

atherogenic dyslipidemia, reduces blood

glucose levels, and reduces HbAlC in

some patients with T2DM. Reductions in

risk factors would suggest that development

of CVD and T2DM would be reduced

with weight loss.38

Approaches for the management of overweight

and obese patients include therapeutic

lifestyle changes (dietary therapy,

physical activity, and behavioral therapy),

pharmacotherapy, and surgery. In-depth

reviews of weight management options

are widely published and are beyond the

scope of this monograph. Various guidelines

on weight management have also

been issued by professional associations,

including the joint publication by the

NHLBI and NAASO.38

Therapeutic Lifestyle

Changes

Two studies in particular show the benefits

of therapeutic lifestyle changes

in reducing intra-abdominal adiposity

and associated risk factors. In the

Studies of Targeted Risk Reduction

Interventions through Defined Exercise

(STRRIDE) trial, Slentz et al117 reported

the first prospective, randomized, controlled

study on the effects of different

amounts of exercise on visceral, subcutaneous,

and total abdominal fat in

a sedentary, middle-aged, overweight population. STRRIDE demonstrated

that even a relatively modest exercise

program (consistent with Centers for

Disease Control [CDC] physical activity

guidelines) prevented significant

increases in visceral fat during the

8-month study. However, a modest

increase in caloric expenditure over

the CDC recommendations resulted

in significant decreases in visceral,

subcutaneous, and total abdominal fat

without changes in caloric intake. In

contrast, continued physical inactivity

in this sedentary overweight population

led to significant gains in visceral fat in

6 months.117

In a study of the effects of lifestyle modification

and pharmacologic intervention

on the metabolic syndrome, Orchard

et al118 reported that intensive lifestyle

modification resulted in a dramatic prevention

of incident metabolic syndrome

and reduction of its overall prevalence.

Of particular interest, these results

appeared to be most strongly related to

a reduction in waist circumference and in

blood pressure, rather than a correction

of the lipid abnormalities of triglycerides

and HDL-C.118 The goals of lifestyle modification

in this study were to achieve and

maintain a weight reduction of at least

7% of body weight through a healthy

low-calorie, low-fat diet and to engage in

physical activity of moderate intensity,

such as brisk walking, for at least 150

minutes per week.

In contrast to these studies, Howard et

al119 reported less promising results from

a Women’s Health Initiative study of a

reduced-fat diet in more than 48,000

postmenopausal women. The dietary

intervention, which reduced total fat

intake and increased intakes of vegetables,

fruits, and grains, achieved only

modest effects on CVD risk factors,

including a small reduction in waist

circumference (89.0 cm to 88.2 cm) at

year 3.119 The diet did not significantly

reduce the risk of coronary heart disease,

stroke, or CVD over a mean followup

of 8.1 years. The authors suggested

that more focused diet and lifestyle interventions

may be needed to improve risk

factors and reduce CVD risk.

Pharmacotherapy

Currently available pharmacologic

approaches to long-term weight management

are primarily limited to appetite

suppression (inhibition of serotoninnorepinephrine-

dopamine reuptake) and

reduction of fat absorption (pancreatic

lipase inhibition). Advancing research

is elucidating other pathways and

physiologic systems involved in the

regulation of energy balance and intraabdominal

adiposity.120

Surgical Approaches

Bariatric weight-loss surgery is an

option for patients with extreme obesity,

providing medically significant

sustained weight loss for more than

5 years in most patients. Reversal

of diabetes, control of hypertension,

marked improvement in mobility, return

of fertility, and significant improvement

in quality of life are common improvements

postsurgery.38 NAASO guidelines

list weight-loss surgery as an option for

patients with severe obesity (BMI ≥40

kg/m2 or ≥35 kg/m2 with comorbid

conditions) in whom other weight-loss

efforts have failed and who are suffering

from the complications of extreme

obesity.38

Perioperative complications vary with

weight and the overall health of the

patient. Mortality rates range from

less than 1% in younger patients with

no comorbidities up to 4% in massively

obese patients with diabetes, hypertension,

and cardiopulmonary failure.38

Complications can include anastomotic

leak, pulmonary embolism, wound infection,

gallstones, and dumping syndrome.

Nutritional deficiencies are not uncommon

following bariatric surgery.

Liposuction is used for cosmetic weight

loss, but evidence shows that liposuction

of abdominal subcutaneous fat (with no

removal of visceral fat) has little effect

on cardiometabolic parameters. In a

study of 15 obese women with normal

glucose tolerance or T2DM, Klein et al121

demonstrated that liposuction of abdominal

subcutaneous adipose tissue did not

improve cardiometabolic risk factors.

There was a 9-10 kg reduction in fat

mass and a 12-14 cm reduction in waist

circumference. Removal of the abdominal

subcutaneous fat had no effect on insulin

resistance, plasma glucose or insulin levels,

plasma adiponectin levels, or any of

the lipid or inflammatory components of

the metabolic syndrome (see Table 5).

In contrast to the liposuction study—and

consistent with the impact of intraabdominal

adiposity on cardiometabolic

risk—experimental studies have reported

that omentectomy with bariatric surgery

in human subjects improved oral glucose

tolerance, insulin sensitivity, and fasting plasma glucose and insulin122 and surgical

removal of visceral adipose tissue in

rats improved insulin sensitivity and insulin

resistance.123

Summary

A wealth of epidemiological, biological,

and mechanistic evidence supports the

active role adipose tissue plays in cardiometabolic

risk. As an endocrine organ,

adipose tissue, specifically visceral

adipose tissue, is a source of free fatty

acids and secretes a variety of adipocytokines

that play key roles in the regulation

of lipid and glucose metabolism and

energy homeostasis. In the settings of

overweight and obesity, accumulation of

intra-abdominal adiposity contributes to

the pathophysiology of multiple cardiometabolic

risk factors through a host of

mechanisms, including increased flux of

free fatty acids in the portal circulation,

dysregulation of multiple adipokines (eg,

adiponectin, leptin, IL-6, TNF-alpha, and

PAI-1), and overactivation of the ECS.

Macrophage infiltration and accumulation

in adipose tissue also promotes obesityassociated

inflammation and its sequelae,

including endothelial dysfunction, insulin

resistance, dyslipidemia, hypertension,

diabetes, and atherosclerosis. Rapidly

advancing scientific research is elucidating

novel pathways and physiologic systems,

including the ECS, that play critical

roles in the regulation of energy homeostasis

and intra-abdominal adiposity.