© The European Society of Cardiology 2008. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Intra-abdominal adiposity, abdominal obesity, and cardiometabolic risk
Ele Ferrannini*,
Anna Maria Sironi,
Patricia Iozzo and
Amalia Gastaldelli
Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Via Roma 67, I-56100 Pisa, Italy
* Corresponding author. Tel: +39 050 553272; fax: +39 050 553235. E-mail address: ferranni{at}ifc.cnr.it
 |
Abstract
|
|---|
Preferential fat deposition in the abdomen—between and
within viscera—has been linked with cardiometabolic risk.
We review data obtained
in vivo in subjects with obesity and/or
diabetes using magnetic resonance imaging (to quantify fat depots),
and positron emitting tomography to quantify glucose uptake
(
18FDG) and blood flow (H
215O) under conditions of euglycaemic
hyperinsulinaemia (clamp technique). Abdominal visceral adipose
tissue (VAT) is small in amount, is dependent on sex, body mass
index, and age and is variably related to waist circumference.
VAT is inherently more insulin-sensitive than subcutaneous fat;
both show impaired glucose uptake in conditions of whole-body
insulin resistance. Furthermore, in VAT, insulin sensitivity
declines with mass and is directly related to blood flow, possibly
reflecting the cellular phenotype of hypertrophic adipose tissue.
Nevertheless, in obesity the expanded fat mass makes a greater
contribution to overall glucose disposal, thereby providing
a compensatory mechanism to the insulin resistance of glucose
metabolism.
Fat accumulation impairs the ability of target tissues to respond to insulin. On the other hand, it provides a safe repository for excess calories and glucose. The balance between the two sides may set individual disease risk. Fat deposition in ‘forbidden’ sites (VAT, liver) signals risk well beyond the amount of fat itself.
Key Words: Abdominal obesity • Adipose tissue • Cardiometabolic risk • Diabetes • Insulin resistance • Obesity • Visceral fat
|
Introduction
|
|---|
Obesity is a potent risk factor for the development of type
2 diabetes and hypertension and complicates their treatment;
1,2 moreover, it is frequently accompanied by dyslipidaemia
3 and
left-ventricular hypertrophy
4 and has been associated with increased
cardiovascular morbidity and mortality.
5 Despite decades of
research, the pathogenetic mechanisms of obesity are still only
partially understood: amount, quality, and location of excess
fat all appear to be important. Also, mounting evidence indicates
that fat tissue is all but an inert depository of calories;
on the contrary, the adipose organ is a highly dynamic reservoir
and a very active tissue both metabolically and hormonally.
6
Preferential fat deposition in the abdomen—between and within viscera and retroperitoneally—has been linked with cardiometabolic risk.7 Measuring the waist girth (or its ratio to the hip circumference) has become a recommended adjunct to clinical examination, and much evidence supports a large waist as a disease risk indicator independent of total adiposity [as the body mass index (BMI)]. We review here information on abdominal visceral adipose tissue (VAT) that may have relevance to its biological impact in man.
|
Quantification
|
|---|
Abdominal VAT can be quantified by imaging tools such as ultrasound,
computerized axial tomography (CAT), and magnetic resonance
imaging (MRI). The latter probably represents the gold-standard
technique, particularly when using multiple cross-sectional
acquisitions. We have applied multislice MRI (as previously
described
8,9) in 72 men and 35 women aged between 24 and 77
years and with BMI ranging from 20 to 40 kg/m
2. By reconstructing
32 0.5-cm transverse sections centred at L
4-L
5, abdominal VAT
and subcutaneous adipose tissue (SAT) were accurately quantified
in an approximately cylindrical volume extending 8 cm both cranially
and caudally to the L
4-L
5 space. This volume encloses >50%
of the abdomen when compared with estimates obtained by helical
computed tomography scans between the upper edge of the liver
and the pelvis.
10 Fat-free mass was measured by electrical bioimpedance;
fat mass was then obtained as the difference between body weight
and fat-free mass.
Despite similar BMI, women had more body fat than men, both in absolute amount and as a percentage of body weight (Table 1). Abdominal fat mass was greater in women, but represented a similar proportion of total fat mass as in men. Of abdominal fat, more was in the subcutaneous compartment in women than men, both in absolute amount and as a percentage of total body fat. VAT, in contrast, was similar in amount in men and women, but represented a significantly higher proportion of total fat mass in the former than in the latter. Furthermore, the VAT/SAT was twice as high in men as in women (Table 1).
These figures indicate that, in adult subjects of either sex
and over a range of age and BMI, only one-fifth of total body
fat is located centrally, i.e. in a region encompassing most
of the abdomen; three quarters of such depot is subcutaneous,
the visceral component averaging
1 kg (or 6% of total fat).
Thus, abdominal VAT is biologically very active but quantitatively
minor. The data also confirm the strong sexual dimorphism of
amount and distribution of adipose tissue. Thus, for the same
BMI, women have more fat than men, overall and in the abdominal
region, within which, however, VAT is relatively more abundant
than SAT in men.
|
Relation to BMI and age
|
|---|
Both VAT and SAT increase with BMI in a quasi-linear manner;
their ratio, however, changes relatively less, indicating a
somewhat proportional accretion of fat in SAT and VAT as overall
fat mass increases in both sexes (
Figure 1). VAT, but not
SAT, increases rather steeply with age, quadrupling over the
25–65-year range (in agreement with previous MRI results
11).
When expressed as a ratio to abdominal fat within the abdomen,
visceral fat increases with age in both women and men in a parallel
fashion but at a similar rate (
Figure 2). Though not longitudinal,
these data do imply that the age-related, progressive rise in
BMI in the general population is characterized by a selective
accumulation of fat in the abdominal viscera.
12 The progressively
more marked physical inactivity of ageing is a plausible correlate
of visceral obesity;
13 however, the exact mechanisms by which
fat is preferentially stored in the visceral depots are not
known.
14
|
Relation to anthropometry
|
|---|
In the clinical settings—or in large-scale studies—visceral
obesity cannot be directly measured by expensive imaging techniques
and is therefore estimated from anthropometric measures (waist
circumference, BMI or the waist-to-hip ratio). This operation
is, however, fraught with errors (as previously noted
11). In
fact, when SAT is plotted against waist circumference, parallel
linear relationships are obtained in men and women. Thus, both
the NCEP-ATP III and the International Diabetes Federation (IDF)
cut-off values (as used in the respective definition of the
metabolic syndrome) correspond to values of SAT mass that differ
by only
0.5 kg between men and women (
Figure 3). In contrast,
a plot of VAT against waist girth yields VAT values that differ
by 2.5–3-fold between sexes with either definition, essentially
because the relationship is significantly steeper in women than
in men (
Figure 4). If the idea behind the separate measurement
of waist circumference and BMI is that the former marks for
additional, weight-independent risk of cardiometabolic abnormalities,
then there are no data available to indicate that such risk
should have widely different thresholds in men and women. Using
the waist-to-hip ratio or BMI does not improve the prediction:
with the former the predicted VAT mass is greater in women than
in men (the contrary of waist alone), whereas using a BMI threshold
of 30 kg/m
2 for both sexes yields VAT estimates that diverge
by more than 1 kg (
Figure 5). Clearly, different data collections—particularly,
in diverse ethnic groups—may generate more or less different
relationships between anthropometric surrogates and the actual
amount of ‘dangerous’ fat. Nevertheless, it seems
unlikely that arbitrarily chosen thresholds might just happen
to converge on any given single VAT value for men and women.
An additional confounder in the relation of anthropometry to
VAT mass is age (e.g.
Figure 2): the sex-adjusted association
between VAT and waist circumference rises from an
r2 of 0.53
to one of 0.68 when also adjusting for age. It should be also
observed that waist girth is a better correlate of SAT (with
an age- and sex-adjusted
r2 of 0.82) than of VAT (
r2 = 0.68).
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 3 Relationship between waist circumference and subcutaneous adipose tissue mass in men (full squares) and women (empty squares). The respective lines of best fit have significantly different intercepts. The dotted projections indicate the sex-specific waist cut-offs according to the NCEP-ATP III and IDF definitions of metabolic syndrome.
|
|
View larger version (24K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 5 Relationship between waist-to-hip ratio (top) or body mass index (bottom) and visceral adipose tissue mass in men and women. Symbols as in Figure 3. The lines of best fit with waist-to-hip ratio have significantly different slopes and intercept, those with body mass index have significantly different slopes.
|
|
A final point is that the relationship between VAT and insulin
sensitivity (i.e. one important metabolic trait) is nonlinear.
For example, in studies where insulin sensitivity was measured
by the euglycaemic hyperinsulinaemic clamp technique and VAT
was assessed by MRI,
15 the relationship between these two variables
was an inverse curvilinear function (
Figure 6). The best
fit of these data predicted that an increase in VAT from 0.5
to 1.8 kg was associated with a 60% decline in insulin sensitivity
(with little further decrease thereafter). The relation of VAT
to different risk factors (e.g. blood pressure) may have completely
different profiles.
View larger version (30K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 6 Reciprocal relationship between abdominal visceral adipose tissue mass (by magnetic resonance imaging) and whole-body insulin sensitivity (by the euglycaemic hyperinsulinaemic clamp technique). Best fit (full line) and 95% confidence intervals (dotted lines) have a correlation coefficient of 0.67. The shaded area encloses the visceral adipose tissue interval over which insulin sensitivity declines most (redrawn from ref. 15).
|
|
Clearly, there is a need to obtain direct VAT measurements in
large population samples, to derive robust allometric equations
to estimate VAT from simple anthropometric variables and finally
to study the formal relationships between VAT and cardiometabolic
risk factors separately in men and women.
|
Metabolic activity
|
|---|
The availability of glucose tracers (deoxyglucose, DG) labelled
with short-lived isotopes (
18F) detectable by positron emitting
tomography (PET) has made it possible to quantify insulin-stimulated
glucose uptake in adipose tissue
in vivo in man. In a series
of studies
15 using
18FDG with PET and MRI to quantify different
fat depots in obese non-diabetic subjects, patients with type
2 diabetes, and healthy controls (
Figure 7), we obtained
the following information on tissue-specific glucose metabolism.
(a) Insulin-mediated glucose uptake by adipose tissues is only
40% that of skeletal muscle (
Figure 8). Considering that
90% of fat-cell volume is lipid, this somewhat unexpected result
implies that fat is metabolically extremely active, far more
than resting muscle in terms of cytoplasmic volume and glycolytic
enzymes. (b) Abdominal VAT is more insulin-sensitive than either
abdominal or femoral SAT. Again, this finding is apparently
at odds with the notion that excess VAT signals disease risk.
In patients with untreated essential hypertension, for example,
VAT accumulation correlates with both insulin resistance and
height of blood pressure.
9 (c) The insulin resistance of skeletal
muscle associated with obesity or type 2 diabetes extends to
adipose tissue in all locations, again with VAT showing higher
rates of glucose uptake than SAT.
View larger version (20K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 7 Anthropometry and fat masses at the whole-body level and in the abdominal region (visceral, subcutaneous, and retroperitoneal) in lean controls, obese non-diabetic subjects, and patients with type 2 diabetes (T2DM) (data from ref. 15).
|
|
View larger version (28K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 8 Tissue-specific insulin-mediated glucose uptake in skeletal muscle and adipose tissue depots (by 18FDG positron emitting tomography scan, expressed per kilogram of tissue) in lean healthy subjects, obese non-diabetic, non-obese diabetic, and obese diabetic subjects (redrawn from ref. 15).
|
|
An additional finding of interest was the relation of tissue-specific
glucose uptake and mass in VAT. When expressed per kilogram
of mass, insulin-mediated VAT glucose uptake was reciprocally
related to VAT mass in a curvilinear fashion (
Figure 9).
In other words, in every mass unit of VAT tissue, glucose uptake
is progressively impaired as the size of the depot increases.
This phenomenon can be explained by assuming that fat accumulation
involves cell hypertrophy first and then hyperplasia (by differentiation
of pre-adipocytes). Thus, as mass increases the adipocyte population
becomes enriched with large, lipid-laden cells. Because large
adipocytes are less insulin-sensitive than small adipocytes,
16 glucose uptake in a unit volume will decrease as the cell phenotype
shifts. Moreover, by combining
18FDG and labelled water (H
215O)
PET scanning to simultaneously measure blood flow and glucose
uptake in the same tissue
17, it was found that in adipose tissue
insulin-mediated glucose uptake is proportional to blood flow,
such that insulin-resistant fat is less perfused than insulin-sensitive
fat (
Figure 10). This observation again resonates with
the notion
18 that blood supply is more abundant in fat depots
rich in small, insulin-sensitive adipocytes. This blood flow/glucose
uptake match is quite different from the physiology of skeletal
muscle—where insulin-mediated glucose uptake is largely
independent of perfusion under resting conditions
19—and
may bear pathogenetic relevance to the association between adiposity
and blood pressure.
20
View larger version (16K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 9 Reciprocal relationship between abdominal visceral adipose tissue mass (by magnetic resonance imaging) and visceral adipose tissue insulin-mediated glucose uptake (by 18FDG positron emitting tomography scan, expressed per kilogram of tissue). Best fit (full line) and 95% confidence intervals (dotted lines) have a correlation coefficient of 0.67. The shaded area encloses the visceral adipose tissue interval over which insulin sensitivity declines most (redrawn from ref. 15).
|
|
View larger version (14K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 10 Relationship between insulin-mediated glucose uptake (by 18FDG positron emitting tomography scan) and blood flow (by H215O positron emitting tomography scan), both expressed per kilogram of tissue in the subcutaneous depot of the leg (redrawn from ref. 15).
|
|
Incidentally, the insulin sensitizing effect of thiazolidinediones
may be in part explained by their effect to promote differentiation
of pre-adipocytes into small, insulin-sensitive fat cells.
21
|
Role in whole-body glucose homeostasis
|
|---|
One counterintuitive consequence of the active participation
of fat mass to overall glucose disposal is illustrated in
Figure 11.
By multiplying tissue-specific glucose uptake by total tissue
mass, the fraction of whole-body glucose disposal that occurs
in skeletal muscle is similar in lean and obese subjects and
in diabetic vs. non-diabetic individuals (which is equivalent
to saying that skeletal muscle insulin resistance quantitatively
parallels to whole-body insulin resistance). In contrast, the
contribution of fat glucose uptake to total glucose disposal
is significantly increased in obesity and diabetes, reaching
20% (viz 50% of muscle) in obese diabetic patients. This is
because the expanded mass of all adipose depots—VAT as
well as SAT (
Figure 7)—provides an additional reservoir
for insulin-mediated glucose uptake despite the insulin resistance.
22
View larger version (41K):
[in this window]
[in a new window]
[Download PowerPoint slide]
|
Figure 11 Fat and skeletal muscle glucose uptake as percent contribution to whole-body glucose disposal in lean and obese subjects, with or without type 2 diabetes. Stars indicate P  0.05 vs. the non-obese, non-diabetic group (recalculated from ref. 15).
|
|
|
Conclusions
|
|---|
The data reviewed here reveal two apparent paradoxes. First,
abdominal VAT is clearly related to cardio-metabolic risk through
a number of emerging mechanisms (adipocytokines, inflammation,
etc.). It is, however, a small depot of very insulin-sensitive
adipocytes. Second, adiposity in general is detrimental to glucose
tolerance but an expanded fat mass serves as a compensatory
response to the glycaemic burden (by providing a metabolic sink
for circulating glucose).
From the metabolic standpoint, fat accumulation has double-edged consequences. On the negative side, it impairs the ability of body tissues to respond to insulin and it stresses the ß-cell. On the positive side, it provides a safe repository for excess calories23 and glucose. The balance between the two sides may differ among subjects, thereby setting individual disease risk. Furthermore, beyond some limit the body reacts to excess fat as a foreign body, and fat deposition in ‘forbidden’ sites (abdominal and thoracic VAT, liver) signals risk well beyond the amount of fat itself. These facts are still incompletely understood and need further research.
|
Funding
|
|---|
European Foundation for the Study of Diabetes—Novo Nordisk
Type 2 Programme Focused Research Grant; the Italian Ministry
of University and Scientific Research (MURST prot. 2001065883_001).
Conflict of interest: none declared.
|
References
|
|---|
- Wilson PW, Meigs JB, Sullivan L, Fox CS, Nathan DM, D'Agostino RB Sr. Prediction of incident diabetes mellitus in middle-aged adults: the Framingham offspring study. Arch Intern Med (2007) 167:1068–1074.[Abstract/Free Full Text]
- Ferrannini E. The phenomenon of insulin resistance: its possible relevance to hypertensive disease. In: Hypertension: Pathophysiology, Diagnosis, and Management—Laragh JH, Brenner BM, eds. (1995) 2nd ed. New York: Raven Press. 2281–2300.
- Després JP. The insulin resistance-dyslipidemic syndrome of visceral obesity: effect on patients’ risk. Obes Res (1998) 16(Suppl. 1):8S–17S.
- Quiñones Galvan A, Galetta F, Natali A, Muscelli E, Camastra S, Ferrannini E. Insulin resistance and hyperinsulinemia: no independent relation to left ventricular mass in humans. Circulation (2000) 102:2233–2238.[Abstract/Free Full Text]
- Hu FB, Willett WC, Li T, Stampfer MJ, Colditz GA, Manson JE. Adiposity as compared with physical activity in predicting mortality among women. N Engl J Med (2004) 351:2694–2703.[Abstract/Free Full Text]
- Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab (2004) 89:2548–2556.[Abstract/Free Full Text]
- St-Pierre J, Lemieux I, Perron P, Brisson D, Santure M, Vohl MC, Després JP, Gaudet D. Relation of the ‘hypertriglyceridemic waist’ phenotype to earlier manifestations of coronary artery disease in patients with glucose intolerance and type 2 diabetes mellitus. Am J Cardiol (2007) 99:369–373.[CrossRef][Web of Science][Medline]
- Positano V, Gastaldelli A, Sironi AM, Santarelli MF, Lombardi M, Landini L. An accurate and robust method for unsupervised assessment of abdominal fat by MRI. J Magn Reson Imaging (2004) 20:684–689.[CrossRef][Medline]
- Sironi AM, Gastaldelli A, Mari A, Ciociaro D, Postano V, Buzzigoli E, Ghione S, Turchi S, Lombardi M, Ferrannini E. Visceral fat in hypertension: influence on insulin resistance and beta-cell function. Hypertension (2004) 44:127–133.[Abstract/Free Full Text]
- Kobayashi J, Tadokoro N, Watanabe M, Shinomiya M. A novel method of measuring intra-abdominal fat volume using helical computed tomography. Int J Obes Relat Metab Disord (2002) 26:398–402.[CrossRef][Web of Science][Medline]
- Ross R, Léger L, Morris D, de Guise J, Guardo R. Quantification of adipose tissue by MRI: relationship with anthropometric variables. J Appl Physiol (1992) 72:787–795.[Abstract/Free Full Text]
- Kohrt WM, Kirwan JP, Staten MA, Bourey RE, King DS, Holloszy JO. Insulin resistance in aging is related to abdominal obesity. Diabetes (1993) 42:273–281.[Abstract]
- Kay SJ, Fiatarone Singh MA. The influence of physical activity on abdominal fat: a systematic review of the literature. Obes Rev (2006) 7:183–200.[CrossRef][Web of Science][Medline]
- Bjorntorp P. Do stress reactions cause abdominal obesity and comorbidities? Obes Rev (2001) 2:73–86.[CrossRef][Medline]
- Virtanen KA, Iozzo P, Hallsten K, Huupponen R, Parkkola R, Janatuinen T, Lonnqvist F, Viljanen T, Ronnemaa T, Lonnroth P, Knuuti J, Ferrannini E, Nuutila P. Increased fat mass compensates for insulin resistance in abdominal obesity and type 2 diabetes: a positron-emitting tomography study. Diabetes (2005) 54:2720–2726.[Abstract/Free Full Text]
- Foley JE, Laursen AL, Sonne O, Gliemann J. Insulin binding and hexose transport in rat adipocytes. Relation to cell size. Diabetologia (1980) 19:234–241.[CrossRef][Web of Science][Medline]
- Virtanen KA, Lonnroth P, Parkkola R, Peltoniemi P, Asola M, Viljanen T, Tolvanen T, Knuuti J, Ronnemaa T, Huupponen R, Nuutila P. Glucose uptake and perfusion in subcutaneous and visceral adipose tissue during insulin stimulation in nonobese and obese humans. J Clin Endocrinol Metab (2002) 87:3902–3910.[Abstract/Free Full Text]
- Crandall DL, DiGirolamo M. Hemodynamic and metabolic correlates in adipose tissue: pathophysiologic considerations. FASEB J (1990) 4:141–147.[Abstract]
- Ferrannini E. Insulin and blood pressure. In: Contemporary Endocrinology: Insulin Resistance. The Metabolic Syndrome X—Reaven GM, Laws A, eds. (1999) Totowa, NJ: Humana Press Inc. 281–308.
- Ferrannini E. The haemodynamics of obesity: a theoretical analysis. J Hypertens (1992) 10:1417.[CrossRef][Medline]
- Viljanen AP, Virtanen KA, Jarvisalo MJ, Hallsten K, Parkkola R, Ronnemaa T, Lonnqvist F, Iozzo P, Ferrannini E, Nuutila P. Rosiglitazone treatment increases subcutaneous adipose tissue glucose uptake in parallel with perfusion in patients with type 2 diabetes: a double-blind, randomized study with metaformin. J Clin Endocrinol Metab (2005) 90:6523–6528.[Abstract/Free Full Text]
- Ferrannini E, Natali A, Bell P, Cavallo-Perin P, Lalic N, Mingrone G. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). J Clin Invest (1997) 100:1166–1173.[Web of Science][Medline]
- Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia (2002) 45:1201–1210.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
Top
Abstract
Introduction
