International Journal of Obesity (2002) 26, Suppl 4, S5–S7
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PAPER
Adipose tissue: a mediator of cardiovascular risk
AM Sharma1*
1
Department of Medicine, McMaster University, Hamilton, Ontario, Canada
Two key findings regarding the cardiovascular risks associated with obesity have emerged in recent years: one relates to the
importance of visceral obesity as a risk factor for cardiovascular disease, and the other to the recognition that adipose tissue can
be regarded as a large endocrine organ that directly contributes to cardiovascular risk by secreting a number of molecules
known to modulate vascular, metabolic, inflammatory and other functional aspects of the cardiovascular system. Therefore,
abdominal fat deposition, which is characterized by increase in waist circumference, should be the target of clinical intervention
in obese individuals.
International Journal of Obesity (2002) 26, Suppl 4, S5 – S7. doi:10.1038/sj.ijo.0802210
Keywords: visceral obesity; adipocyte; leptin; cardiovascular risk
Introduction
Obesity is a key risk factor for the development of cardiovascular disease, second only to cigarette smoking. Even a modest
increase in body weight (body mass index (BMI) 30 kg=m2)
results in a four-fold increase in the risk of cardiovascular
disease in both men and women1 (Figure 1).
In 1988, the American Heart Association reclassified obesity as a major, modifiable risk factor for coronary heart
disease.2 This represented a step forward from the earlier
belief that obesity contributed to heart disease primarily
through obesity-related covariates such as hypertension, dyslipidaemia and impaired glucose tolerance or type 2 diabetes.
In recent years, it has become increasingly clear that the
distribution of adipose tissue is important when considering
the risks of obesity. Cardiovascular and metabolic risk is
more closely correlated to ‘android’ obesity (visceral obesity
or upper body obesity) than to ‘gynoid’ obesity (lower body
obesity). This was first suggested in 1947 by the French
physician Jean Vague and was more recently shown in a
number of studies. For example in the prospective Honolulu
Heart study,3 which followed almost 8000 men over 12 y
(Figure 2), the risk of coronary artery disease was as high in
the non-obese group with visceral obesity as it was in obese
individuals with visceral obesity. In contrast, obese individuals with lower body obesity had a minimal increase in risk
*Correspondence: AM Sharma, Canada Research Chair for Cardiovascular
Obesity Research and Management, McMaster University, Hamilton
General Hospital, Ontario, Canada L8L 2X2.
E-mail: [email protected]
compared with non-obese individuals with lower body
obesity. This shows the importance of focusing attention
on visceral obesity, as it is this fat that contributes most to
the development of cardiovascular disorders.
Visceral obesity refers to the accumulation of adipose
tissue within the abdomen. Abdominal fat deposition is
characterized by an increase in waist circumference, and
this measurement is better than BMI as an indicator of
cardiovascular and metabolic risk.4,5
Insulin-resistant adipocytes
There are both anatomical and metabolic differences
between abdominal and subcutaneous adipose tissue. Intraabdominal adipose tissue is not only more metabolically
active,6 but also contains large insulin-resistant adipocytes
while adipose tissue associated with lower body obesity
contains small, insulin-sensitive adipocytes.7 The adrenergic
control of adipose tissue also differs in that the large
adipocytes found in abdominal adipose tissue have a
higher density of adrenergic receptors than the small cells
in lower body obesity.
The combination of decrease in insulin-mediated antilipolysis and increase in catecholamine-mediated lipolysis in
abdominal adipose tissue results in increased circulating
levels of non-esterified fatty acids in plasma. This has been
shown in metabolic studies in which plasma concentration
of free fatty acids, plasma free fatty acid turnover rate and
hepatic glucose production were all higher in individuals
with abdominal obesity than those with lower body obesity
or controls.8
Adipose tissue
AM Sharma
S6
Figure 1 Cardiovascular mortality at different levels of body mass
index. Source: Stevens et al.1
Figure 3 Factors contributing to cardiovascular risk in patients with
visceral obesity.
These metabolic aspects of abdominal adipose tissue are
not the only contributors to cardiovascular risk. Visceral
obesity is also associated with hypertension, renal hyperfiltration, increased inflammatory response, increase in prothrombotic factors, endothelial dysfunction and several lipid
abnormalities (Figure 3). All of these factors can contribute
to the development of cardiovascular disease and end-organ
damage in obese patients.
Until recently, the adipocyte was largely thought to be an inert
storage cell whose main function was to store excess energy in
the form of triglycerides. It is now apparent that adipocytes
have a more complex role in the organism. Thus, adipocytes
produce a large number of hormones, peptides and smaller
molecules that impact on metabolism and on cardiovascular
regulation, not only in an autocrine and paracrine manner but
also in an endocrine manner. This supports the view that
adipose tissue must be regarded as an endocrine organ.9
One of the key vasoactive substances produced by adipocytes is leptin, which is an important regulator of food
intake. Leptin acts at the level of the hypothalamus and
down-regulates neuropeptide Y, leading to decreased hunger,
increased activity and increased thermogenesis. It is also
associated with an increase in sympathetic activity.10
Infusion of leptin into the carotid artery of dogs results
in a dose-dependent increase in both arterial pressure and
heart rate.11
There are also a number of studies in man showing good
correlation between plasma leptin levels and heart rate.12
Hence, leptin derived from adipose tissue drives sympathetic
activity, which in turn contributes not only to volume retention (one of the hallmarks of obesity), but also to an increase
in heart rate, resulting in the increase in cardiac output and
blood pressure characteristic of obesity. Figure 4 summarizes
the central effects of leptin.
The adipocyte also appears to express all components of
the renin-angiotensin system,13 and this system is now
believed to play an important role in the differentiation of
the adipocyte.14
In recent biopsy studies, we have demonstrated a correlation between 24 h blood pressure and the expression of genes
related to the renin – angiotensin system (angiotensin
converting enzyme and angiotensin type 1 receptor
genes) in human adipocytes.15 This suggests that the
renin – angiotensin system of adipose tissue might be
involved in the aetiology of obesity-related hypertension.
Other adipocyte-derived molecules, including prostaglandins, adiponectin16 and the more recently discovered molecule resistin,17 affect metabolic function and might have a
Figure 2 Effect of pattern of obesity on risk of coronary artery disease — the Honolulu Heart Study. Source: Donahue et al.3
Figure 4
Adipose tissue as an endocrine organ
International Journal of Obesity
The central effects of leptin.
Adipose tissue
AM Sharma
Figure 5 The potential benefit of moderate (5 – 10%) weight loss.
Source: Despres et al.21
role in the regulation of cardiovascular end organ damage.
Thus, leptin has been shown to enhance calcification of
vascular smooth muscle cells.18 We have also recently
demonstrated that perivascular adipose tissue releases a
factor that significantly modulates vascular response to constrictive stimuli.19
In addition, obese individuals have high circulating
plasma levels of a range of inflammatory markers and
thrombogenic factors produced by adipose tissue including
TNF-alpha,20 interleukin-1 and fibrinogen. These factors,
which can be reduced by weight loss, are likely to contribute
to vascular damage in obese individuals.
Thus, the picture that is emerging is that adipose tissue
itself is the source of many of the metabolic and cardiovascular abnormalities that determine the increased cardiovascular risk associated with obesity.
Conclusion
Abdominal adipose tissue carries the greatest metabolic and
cardiovascular risk for patients and it is clear that we need to
target abdominal obesity in treating obese patients. Even a
modest weight reduction of 5 – 10% can lead to marked
reductions in blood pressure, susceptibility to thrombosis,
and inflammatory markers and to a marked improvement in
the lipid profile and insulin sensitivity, as shown in Figure 5.21
References
1 Stevens J, Cai J, Pamuk ER, Williamson DF, Thun MJ, Wood JL.
The effect of age on the association between body-mass index and
mortality. New Engl J Med 1998; 338: 1 – 7.
2 Eckel RH, Krauss RM. American Heart Association call to action:
obesity as a major risk factor for coronary heart disease. AHA
Nutrition Committee. Circulation 1998; 97: 2099 – 2100.
3 Donahue RP, Abbott RD, Bloom E, Reed DM, Yano K. Central
obesity and coronary heart disease in men. Lancet 1987; 1:
821 – 824.
4 Lean ME, Han TS, Seidell JC. Impairment of health and quality of
life in people with large waist circumference. Lancet 1998; 351:
853 – 856.
5 Lemieux I, Pascot A, Couillard C, Lamarche B, Tchernof A,
Almeras N, Bergeron J, Gaudet D, Tremblay G, Prud’homme D,
Nadeau A, Despres JP. Hypertriglyceridemic waist: A marker of the
atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation 2000; 102(2):
179 – 184.
6 Arner P. Differences in lipolysis between human subcutaneous
and omental adipose tissues. Ann Med 1995; 27: 435 – 438.
7 Bjorntorp P. Metabolic difference between visceral fat and
subcutaneous abdominal fat. Diabetes Metab 2000; 26(Suppl 3):
10 – 12.
8 Jensen MD, Haymond MW, Rizza RA, Cryer PE, Miles JM. Influence of body fat distribution on free fatty acid metabolism in
obesity. J Clin Invest 1989; 83: 1168 – 1173.
9 Engeli S, Sharma AM. Role of adipose tissue for cardiovascular –
renal regulation in health and disease. Horm Metab Res 2000; 32:
485 – 499.
10 Haynes WG. Interaction between leptin and sympathetic nervous
system in hypertension. Curr Hypertens Rep 2000; 2: 311 – 318.
11 Shek EW, Brands MW, Hall JE. Chronic leptin infusion increases
arterial pressure. Hypertension 1998; 31: 409 – 414.
12 Narkiewicz K, Kato M, Phillips BG, Pesek CA, Choe I, Winnicki M,
Paltini P, Sivitz WI, Somers VK. Leptin interacts with heart rate
but not sympathetic nerve traffic in healthy male subjects.
J Hypertens 2001; 19: 1089 – 1094.
13 Engeli S, Negrel R, Sharma AM. Physiology and pathophysiology
of the adipose tissue renin-angiotensin system. Hypertens 2000;
35: 1270 – 1277.
14 Janke J, Engeli S, Gorzelniak K, Luft FC, Sharma AM. Mature
adipocytes inhibit in vitro differentiation of human preadipocytes
via angiotensin-type 1 receptors. Diabetes 2002; 51: 1699 – 1707.
15 Gorzelniak K, Engeli S, Janke J, Luft FC, Sharma AM. Hormonal
regulation of the human adipose-tissue renin – angiotensin
system: relationship to obesity and hypertension. J Hypertens
2002; 20: 965 – 973.
16 Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y,
Hotta K, Nishida M, Takahashi M, Nakamura T, Yamashita S,
Funahashi T, Matsuzawa Y. Novel modulator for endothelial
adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999; 100: 2473 – 2476.
17 Shuldiner AR, Yang R, Gong DW. Resistin, obesity and insulin
resistance — the emerging role of the adipocyte as an endocrine
organ. New Engl J Med 2001; 345: 1345 – 1346.
18 Parhami F, Tintut Y, Ballard A, Fogelman AM, Demer LL. Leptin
enhances the calcification of vascular cells: artery wall as a target
of leptin. Circul Res 2001; 88: 954 – 960.
19 Lohn M, Dubrovska G, Lauterbach B, Luft FC, Gollasch M,
Sharma AM. Periadvential fat releases a vascular relaxing factor.
FASEB J 2002; 16: 1057 – 1063.
20 Samad F, Uysal KT, Wiesbrock SM, Pandey M, Hotamisligil GS,
Loskutoff DJ. Tumor necrosis factor alpha is a key component in
the obesity-linked elevation of plasminogen activator inhibitor 1.
Proc Natl Acad Sci USA 1999; 96: 6902 – 6907.
21 Despres J-P, Lemieux I, Prud’homme D. Treatment of obesity:
need to focus on high risk abdominally obese patients. Br Med J
2001; 332: 716 – 720.
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International Journal of Obesity