International Journal of Obesity (2004) 28, 228–233
& 2004 Nature Publishing Group All rights reserved 0307-0565/04 $25.00
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PAPER
Subcutaneous adipose tissue blood flow varies
between superior and inferior levels of the anterior
abdominal wall
J-L Ardilouze1, F Karpe1, JM Currie1, KN Frayn1 and BA Fielding1*
1
Oxford Centre for Diabetes, Endocrinology and Metabolism, Nuffield Department of Clinical Medicine, Churchill Hospital,
Oxford, UK
OBJECTIVE: Blood flow regulation is thought to mediate the metabolic functions of adipose tissue. Different depots, and even
different layers within the subcutaneous adipose tissue, may vary in metabolic activity and blood flow. Therefore, we
investigated if any differences in subcutaneous adipose tissue blood flow (ATBF) exist at different locations of the anterior
abdominal wall.
METHODS: ATBF was measured 8–10 cm above or below the umbilicus, at 8–10 cm (both sides) from the midline, in 18 healthy
subjects (BMI range 18–33 kg/m2). Measurements of ATBF were performed using 133xenon washout, during a stable baseline
period and after ingestion of 75 g of glucose.
RESULTS: At baseline, ATBF was greater at the upper level compared to the lower level (4.470.3 vs 3.870.2 ml min1 100 g
tissue1, P ¼ 0.005), but was not different between the right and the left sides at either level. ATBF increased in response to oral
glucose at all sites. The mean increase at the superior level was also greater than the inferior level (3.570.7 vs 2.270.6 ml min1
100 g tissue1, P ¼ 0.001).
CONCLUSIONS: Even at a constant depth and with only 16–20 cm difference between sites, there are significant differences in
function of the same adipose depot. These findings have physiological and methodological implications for in vivo metabolic
studies of human adipose tissue.
International Journal of Obesity (2004) 28, 228–233. doi:10.1038/sj.ijo.0802541
Published online 25 November 2003
Keywords: regional blood flow; humans; insulin; microinfusion; adipose tissue
Introduction
As well as an active site of the regulation of lipid storage,
adipose tissue is recognized to have important metabolic and
endocrine roles, particularly as the principal site of leptin
and adiponectin production.1 In order to fulfil these roles,
adequate perfusion of adipose tissue is required, and
impaired regulation of adipose tissue blood flow (ATBF) has
been linked to obesity and insulin resistance.2–5 Metabolic
abnormalities have been associated with regional adiposity.5–
9
In particular, elevated postabsorptive and postprandial
nonesterified fatty acid concentrations are found in upper
body/viscerally obese humans.10 These higher concentra-
*Correspondence: BA Fielding, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ –UK.
E-mail: [email protected]
Received 18 June 2003; revised 3 September 2003; accepted 5 October
2003
tions are due to increased rates of adipose tissue lipolysis and
are associated with hypertension, dyslipidemia and type II
diabetes.
Studies of in vivo function of adipose tissue in man have
utilized techniques such as arterio-venous difference, 133xenon washout for the measurement of ATBF, microdialysis
and more recently, microinfusion.11 Most of these techniques investigate the subcutaneous adipose tissue at a defined
depth, usually up to 10 mm. However, it has recently been
reported that a fascia divides subcutaneous abdominal
adipose tissue into two layers and that only the deeper layer
is strongly related to insulin resistance.6,8 In the superficial
layer, it has been shown that the lipolytic rate was higher
than the preperitoneal adipose tissue,7 and that the ATBF
was more responsive to a stimulus of adrenaline than the
deep layer.7 However, no differences in insulin absorption
were found between superficial and deep subcutaneous
adipose tissue.12,13
Variation in subcutaneous adipose tissue blood flow
J-L Ardilouze et al
229
It has been shown that the subcutaneous absorption of
insulin varies according to adipose tissue depots, in nondiabetic14 and diabetic 12,13,15 subjects. These differences
have been found to correlate with blood flow in some
studies16–19 but not others.20–23 Within the abdominal
subcutaneous adipose tissue depot, insulin absorption has
been shown to be faster in the upper, epigastric area
compared with lower sites of the abdomen12 but no
differences in ATBF were found between the two sites.23
However, the xenon washout technique used in that paper to
measure ATBF has since been improved by using g counters
attached to the skin.24
In this study, we hypothesize that the metabolic functions
of abdominal subcutaneous adipose tissue may vary between
the upper and lower areas. We have therefore measured
superior and inferior ATBF in the anterior abdominal wall,
using a sensitive method25 during a sustained baseline
period, and after the ingestion of oral glucose.
Materials and methods
Study design
Healthy volunteers were asked to refrain from strenuous
exercise or alcohol intake 24 h before the experiment and,
following an overnight fast, were studied at rest, in supine
position, in a temperature-controlled room at 241C. A 22-g
cannula (Becton Dickinson, Franklin Lakes, NJ, USA) was
inserted retrogradely into a distal forearm vein and kept
patent by continuous slow infusion of saline (NaCl, 9 g/l).
The hand was heated to provide arterialized blood samples.
After taking two baseline samples (15 min apart), samples
were taken at 30 min intervals into refrigerated heparinized
tubes and immediately placed on ice. The plasma was
separated at þ 41C and frozen within 15 min. At 60 min,
75 g glucose in water was ingested to stimulate endogenously
regulated ATBF.
Biochemical measurements
Plasma glucose was measured the same day on samples
stored at þ 41C using an enzymatic method.26 The remaining plasma was stored at 201C for measurement of
nonesterified fatty acids (NEFA) (WAKO NEFA C kit, Alpha
Laboratories, Eastleigh, UK) and triacylglycerol (TAG) (Randox Laboratory, Crumlin, UK) concentrations by enzymatic
methods. Plasma insulin was measured by a double antibody
radioimmunoassay (Pharmacia and Upjohn, Milton Keynes,
UK).
ATBF quantitation protocol
ATBF was measured simultaneously at four sites (superior
and inferior, right and left) in the subcutaneous adipose
tissue of the anterior abdominal wall, 8–10 cm above or
below the umbilicus at approximately 8–10 cm from the
midline. The exact location was at one third of the distance
between the midline and the external side of the abdomen.
In brief, four small cannulae, 6 mm long, designed for the
continuous delivery of insulin (‘Soft-set’ infusion set,
Medtronic, Applied Medical Technology Ltd, Cambridge,
UK; dead volume 60 ml) were inserted into the abdominal
subcutaneous tissue. This device ensured that all blood flow
measurements were made at approximately the same depth,
with 15–80 ml 133xenon distributing in a tissue volume of
about 1 ml.3,27 A saline infusion (CMA pumps, Sunderland,
UK) was immediately started at 2 ml min1. After allowing
20 min for the tissue to recover, 0.5–1.0 MBq 133xenon was
injected directly through the port in the hub of each catheter
and a g-counter probe (Oakfield Instruments, Eynsham, UK)
placed over the site of injection and firmly taped in place.
The cannulae were perfused for 1 min at 60 ml min1 with
saline to wash the 133xenon through the dead volume, and
for a further 40–60 min at 2 ml min1 to allow for equilibration (ie to allow for the disappearance of the hyperaemia and
the diffusion/equilibration of the xenon into the tissue).
After 20 min baseline recording, an extended baseline period
of 60 min was recorded in half of the probes (the other
probes were used for drug infusion studies, which are
reported elsewhere28). At time þ 60 min the subject was
given the 75 g oral glucose in 200 ml of lemon-flavoured
water, while infusions continued for a further 120 min.
The Oxfordshire Clinical Research Ethics Committee
approved the studies, which conformed to the Declaration
of Helsinki, and all subjects gave informed consent.
Calculations and statistics
Statistical analyses were performed with SPSS for Windows
Release 11.5. (SPSS Inc., Chicago, IL, USA). Analytical data
are expressed as mean7standard error of the mean (s.e.m.)
or median and range. Xenon counts were recorded continuously and blood flow was calculated in consecutive
10 min time periods, as previously described, using a
partition coefficient for xenon between adipose tissue and
blood of 10 ml g1.11 Baseline ATBF was calculated as the
mean of the time points 15 and 5 min and the extended
baseline was calculated as the mean of the time points from
5 to 55 min. Coefficients of variation (CV) were calculated
from duplicate measurements of ATBF. The ‘peak’ ATBF value
is the mean of the three contiguous points that gave the
highest mean value after glucose ingestion.11 The ‘response
to glucose’ was analyzed as peak minus baseline ATBF. The
ATBF peak/baseline ratio was also calculated in order to
remove the effect of the partition coefficient on the blood
flow results.
Insulin sensitivity indices for glucose (ISIgly) and NEFA
suppression (ISINEFA) were calculated as follows:
ðISIgly Þ ¼ 2=ððINSpGLYpÞ þ 1Þ
ðISINEFA Þ ¼ 2=ððINSpNEFApÞ þ 1Þ
where INSp, GLYp and NEFAp are insulin, glucose and NEFA
area under the curve, respectively, over 2 h after glucose
ingestion, expressed relative to average values from the
International Journal of Obesity
Variation in subcutaneous adipose tissue blood flow
J-L Ardilouze et al
230
Results
Characteristics of subjects
A total of 18 healthy volunteers (10 female subjects) were
studied. The median age was 30.6 y (range 19–48), median
BMI was 22.8 kg/m2 (range 18–33), mean systolic BP was
10672 mmHg and mean diastolic BP was 6572 mmHg.
Table 1 Baseline subcutaneous ATBF at four sites of the anterior abdominal
wall (n ¼ 18)
Superior
Inferior
Right
Left
Overall
4.470.3*
3.870.3*
4.570.4*
3.770.3*
4.470.3
3.870.2w
Data were recorded 8–10 cm above (superior) or below (inferior) the
umbilicus at approximately 8–10 cm from the midline. Significant differences
are indicated as w(Po0.005, paired t-test) between superior and inferior levels
and as * (P ¼ 0.006, repeated measures analysis of variance) between the four
sites. Values are mean and s.e.m. and given in ml min1 100 g tissue1.
a
8
rs = 0.74
7
ATBF (left side)
group of subjects.29 With this method, ISI(gly) and ISI(NEFA)
are obtained under rather physiological conditions, not
under artificially induced steady state as during a euglycaemic clamp. A higher value of ISIgly indicates greater insulin
sensitivity.
For the baseline results, data were calculated from the four
adipose tissue sites in 18 subjects. The extended baseline
period and responses to the meals were obtained from two
sites for each subject, one from the superior level, the other
one from the inferior level. Data from left and right sites
were therefore combined in order to compare responses
between superior and inferior adipose tissue areas.
The differences in baseline ATBF between the four sites
were analyzed using repeated measures analysis of variance.
The difference between baseline and extended baseline, and
between postprandial ATBF responses were tested using
paired t-tests. Spearman’s rank correlation coefficients were
calculated to assess relationships between the four sites.
P < 0.001
6
5
4
3
2
1
0
0
1
Baseline ATBF
Baseline blood flow recordings were stable; there were
no statistical differences in ATBF between time points 15
and 5 min, mean values were 4.3970.39 and
4.4070.23 ml min1 100 g tissue1, respectively. When expressed as a CV, the two baseline values varied by 15.9%.
The measurements for baseline ATBF were significantly
different at the four sites when tested by repeated measures
analysis of variance (Table 1). There were no significant
differences in baseline ATBF between right and left sides for
both superior and inferior sites (Table 1). ATBF was
significantly correlated between right and left sites
(rs ¼ 0.74, Po0.001 and rs ¼ 0.65, P ¼ 0.004 for superior
(Figure 1a) and inferior sites, respectively). The CV, calculated from the paired data from left and right sides, for
superior and inferior sites were 16.4 and 18.1%, respectively.
Baseline ATBF was higher in the superior sites for both left
and right sides (Table 1). ATBF was significantly correlated
International Journal of Obesity
ATBF (superior site)
4
5
6
7
8
6
7
8
ATBF (right side)
b
Systemic responses
Fasting plasma glucose (4.9570.07 mmol l1), insulin
(5.0370.54 mU l1), TAG (8737121 mmol l1) and NEFA
(540743 mmol l1) were stable during the baseline period
and up to 60 min. After ingestion of glucose, plasma
concentrations of glucose and insulin increased, whereas
NEFA decreased. The values corresponded to those expected
from normal subjects (data not shown).
3
2
8
rs = 0.71
7
P = 0.001
6
5
4
3
2
1
0
0
1
2
3
4
5
ATBF (inferior site)
Figure 1 Relationships between baseline ATBF (ml min1 100 g adipose
tissue1) in adipose tissue sites of the anterior abdominal wall. Blood flow was
measured simultaneously in 18 subjects at four sites in the subcutaneous
adipose tissue, that is 8–10 cm above or below the umbilicus at 8–10 cm from
the midline (see text for details). The scattergrams show the relationships
between left and right sides in the superior site only (a), and between inferior
and superior sites on the left side only (b). Other significant correlations are
reported in the results section.
between superior and inferior sites (rs ¼ 0.58, P ¼ 0.016 and
rs ¼ 0.71, P ¼ 0.001 for right and left (Figure 1b) sides,
respectively). At each site, ATBF was stable during the
extended period.
Variation in subcutaneous adipose tissue blood flow
J-L Ardilouze et al
231
Figure 2 Fasting and postprandial responses of subcutaneous ATBF 8–10 cm
above (K) or below (J) the umbilicus in healthy subjects. Data show mean
values from left and right sides (at approximately 8–10 cm from the midline).
Oral glucose was given at time þ 60 min to stimulate endogenously regulated
blood flow. Values are mean (s.e.m.).
Postprandial ATBF
ATBF increased in response to oral glucose at both superior
and inferior sites (Figure 2). The mean response to glucose at
the superior sites (3.570.7 ml min1 100 g tissue1) was
significantly higher than the response at the inferior sites
(2.270.6 ml min1 100 g tissue1, P ¼ 0.001). There was a
significant correlation between ATBF response at the superior and inferior sites (rs ¼ 0.85, Po0.001, Figure 3). The peak/
baseline ratio in the superior site was significantly higher
than the ratio in the inferior site (2.070.1 vs
1.770.1 ml min1 100 g tissue1, P ¼ 0.05) in lean subjects
(n ¼ 10, BMI o 25 kg/m2).
ATBF and its relationship to insulin sensitivity
Since baseline ATBF and ATBF response at the superior level
showed differences compared with the inferior level, a
relationship with insulin sensitivity indices was sought at
the two levels. There were no correlations between baseline
ATBF and insulin sensitivity indices for either superior or
inferior sites. However, the ATBF response to glucose at the
superior level was negatively correlated with BMI (rs ¼ 0.62,
P ¼ 0.011) and positively correlated with both insulin
sensitivity indices, ISIgly (rs ¼ 0.61, P ¼ 0.016) and ISINEFA
(rs ¼ 0.71, P ¼ 0.003). The ATBF increase at the inferior level
was associated with ISINEFA only (rs ¼ 0.55, P ¼ 0.032). Further
analyses of the relationship between ISINEFA and ATBF
showed similar regression slopes for both levels and any
difference in the strength of the association was largely
explained by the smaller ATBF response at the inferior level.
Discussion
We have shown that the mean baseline blood flow, measured
in subcutaneous adipose tissue of healthy subjects after an
overnight fast, is 16% higher in the superior or upper areas of
Figure 3 Relationship between the ATBF response (ml min1 100 g adipose
tissue1) to oral glucose in the inferior and superior sites of the anterior
abdominal wall. Blood flow was measured as in Figure 1; ATBF response to oral
glucose was calculated as peak-baseline (see Materials and methods). The
scattergram shows the relationships between inferior and superior sites on the
left side.
abdominal anterior wall compared with inferior or lower
areas. After glucose ingestion, which was given to increase
blood flow,25 mean ATBF and ATBF response were greater by
25 and 60%, respectively, in the superior sites. No differences
were observed when comparing baseline blood flow in left
and right sides. In fact, the amount of variation observed
between baseline ATBF measurements at the left and right
sides was similar to that observed during consecutive baseline measurements. The minimal variation (methodological
plus biological) of ATBF was 16%. In comparison, the day-today variability of baseline subcutaneous ATBF has been
found to be significantly greater than within-day variation.30
In agreement with our previous findings,3 a relationship
between insulin sensitivity indices and ATBF responsiveness
was found. ISINEFA was associated with ATBF response to
glucose at both levels and we also found a correlation
between ISIgly and blood flow response at the superior level.
These associations appear to be stronger for the superior
level, but this can be explained by the difference in
magnitude of the ATBF responses.
Our data are in agreement with the heterogeneity in
function that has been described both between and within
adipose tissue depots. Their interest stems from the associations of different depots with insulin resistance and
increased risk of diabetes and cardiovascular disease. The
associations between blood flow, metabolic activity and
disease risk are not, however, straightforward. In general,
upper-body fat depots are more metabolically active than
those in the lower body, and more strongly associated with
insulin resistance and cardiovascular disease risk.31 Within
each depot, however, the relationships are more complex.
The deeper layers of subcutaneous fat are more strongly
associated with insulin resistance than are the more superInternational Journal of Obesity
Variation in subcutaneous adipose tissue blood flow
J-L Ardilouze et al
232
ficial layers,6,8 yet lipolysis is greater in the more superficial
layers.7 The preperitoneal depot (immediately superficial to
the peritoneum) is also less active than the superficial fat7
and yet anatomically is closer to the intraabdominal depots,
which in many studies correlate more strongly with insulin
resistance.32,33 Here, we show that even at a similar depth
within one depot, there are significant and systematic
differences in function in different areas separated by only
16–20 cm. We speculate that perhaps there is generally a
gradient in adipose tissue metabolic activity and blood flow
from superior to inferior34 and that this may apply within
depots as well as across different depots.
It could be argued that the observed differences in baseline
ATBF are partly due to differences between the superior and
inferior sites in partition coefficient for 133xenon. The
partition coefficient for 133xenon has been found to be
8.271.2 in the subcutaneous tissue of the abdomen and the
thigh, in a cohort of subjects similar to ours.35 A difference
between lean and obese subjects was found when the
partition coefficient was estimated from needle biopsies
taken from the subcutaneous abdominal adipose tissue:
8.6 ml g1 in lean subjects and 9.9 ml g1 in obese subjects.36
However, an average value is usually taken when comparing
adipose tissue depots7,37 because of the difficulty of determining partition coefficients in vivo. For our calculations of
ATBF, we assumed for all sites a partition coefficient of
10 ml g1.11,24,38,39 In lean subjects, in whom the most
marked ATBF response was seen, the comparison of the
peak/baseline ratio between superior and inferior sites was
statistically significant, indicating that a difference exists
when the confounding effect of partition coefficient is
removed. The comparison did not reach significance when
overweight subjects were included probably because the
response to glucose is blunted in obese people.2,25 Therefore,
we conclude that the differences in ATBF response to glucose
ingestion reflect true functional differences.
It could also be argued that our data reflect differences
between the superficial and the deep layer of the abdominal
subcutaneous adipose tissue. The thickness of the superficial
layer in each individual is relatively constant40 and accounts
for 60% of the subcutaneous adipose tissue thickness.41 For
our experiments, 133xenon was always injected at the same
depth, that is at the end of the catheter. Accordingly, we
assume that our measurements were performed in the same
subcutaneous adipose tissue layer for each subject.
Our data, obtained using a robust technique (as demonstrated in this study by close correlation of ATBF at different
sites within subjects), support a study that demonstrated a
difference in absorption of soluble insulin between the upper
and the lower part of the abdomen,12,23 but failed to
demonstrate a link with blood flow.23
In summary, we have shown that blood flow is higher in
the upper areas of the abdominal anterior wall compared
with lower areas, in the resting state as well as after glucose
stimulation. These differences have clear methodological
implications for in vivo studies of human adipose tissue if
International Journal of Obesity
multiple measurements are required, for instance studies
with several microdialysis probes or microinfusion sets
placed at different levels on the abdomen. These differences
within one depot also need to be taken into account in
studies comparing different adipose tissue depots.
Acknowledgements
We thank the Wellcome Trust for financial support
Note added in proof
Since the submission of this paper, it has come to our
attention that the following paper has been published, in
agreement with our findings of higher ATBF in an upper
site of the subcutaneous adipose tissue. Simonsen L,
Enevoldsen LH and Bülow J. Determination of adipose tissue
blood flow with local 133 Xe clearance. Evaluation of a
new labelling technique. Clin Physiol Funct Imaging 2003; 23:
320–323.
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