The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 3 760-764
Copyright © 1997 by The Endocrine Society
Visceral Adipose Tissue Is Associated with Circulating High Affinity Growth Hormone-Binding Protein
Corné A. M. Roelen,
Hans P. F. Koppeschaar,
Wouter R. de Vries,
Yvonne E. M. Snel,
Manorath E. Doerga,
Pierre M. J. Zelissen,
Jos H. H. Thijssen and
Marinus A. Blankenstein
Department of Endocrinology, University Hospital Utrecht, and the
Department of Medical Physiology and Sports Medicine, Utrecht
University (W.R.d.V.), Utrecht, The Netherlands
Address all correspondence and requests for reprints to: Hans P. F. Koppeschaar, M.D., Ph.D., Department of Endocrinology, University Hospital Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
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Abstract
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Recent data show that body fat distribution, specifically visceral fat
accumulation, is associated with the regulation of GH secretion. To our
knowledge no studies have been performed with regard to the
relationship between plasma high affinity GH-binding protein (GHBP)
levels and fat distribution in humans. To address this question, we
measured plasma GHBP and insulin-like growth factor I levels as well as
visceral, sc abdominal, and hip adipose tissue (AT) areas by using
magnetic resonance imaging scanning in 12 patients with GH deficiency
(GHD) and in 12 age- and sex-matched healthy subjects. The GHD patients
were subsequently treated with GH replacement therapy. Regardless of
the GH status of the subjects, body mass index and visceral AT area
were positively correlated to plasma GHBP (r = 0.70;
P < 0.01 and r = 0.73; P
< 0.01, respectively), whereas the sc AT areas at the abdominal level
tended to correlate positively with GHBP levels, but did not reach
significance (r = 0.44; P = 0.07). The sc AT
areas at the hip level were not correlated with plasma GHBP levels. In
the GHD patients the pretreatment visceral and abdominal sc AT areas
were positively correlated with the change in GHBP levels after GH
replacement (r = 0.82; P < 0.01 and r =
0.75; P < 0.01, respectively). The pretreatment sc
AT area at the hip level was not associated with the therapy-induced
changes in plasma GHBP (r = 0.28; P > 0.10).
In summary, this study shows that visceral fat is associated with
circulating GHBP levels, suggesting that visceral fat mass may be
involved in the regulation of the plasma GHBP level. Further, the
amount of abdominal fat in GHD patients may partially determine the
plasma GHBP response to GH replacement therapy.
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Introduction
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GH SECRETION is influenced by physical
characteristics, such as age, sex, and adiposity (1, 2). Furthermore,
GH plays a role in regulating fat mass by its lipolytic effect (3, 4).
Studies from several research groups have emphasized the importance of
regional adipose tissue distribution as a correlate of the metabolic
complications that can be observed in obesity. For example, in visceral
obesity, there is a high prevalence of insulin resistance,
hyperinsulinemia, glucose intolerance, dyslipidemia, and hypertension
(5, 6, 7, 8). It is also known that in obesity pulsatile GH secretion is
markedly diminished (9). GH-binding protein (GHBP) levels are high in
patients with obesity (10, 11). As circulating GHBP may be regarded as
an intrinsic part of the GH/insulin-like growth factor I (IGF-I) axis,
an effect of body composition on circulating GHBP levels may be
expected. In general, positive correlations between body mass index
(BMI) and plasma GHBP levels were observed (11, 12, 13, 14, 15, 16). Recently, we
reported that GH-deficient (GHD) adults have an increased visceral fat
mass compared to healthy subjects matched for age and sex (17). To our
knowledge no studies have been reported that investigated the
association between fat distribution and circulating GHBP in humans.
The aim of this study was to investigate the relationship between
plasma GHBP and visceral adipose tissue (AT) areas, sc AT areas at the
level of the abdomen and hip, as assessed by magnetic resonance imaging
(MRI) scanning, in patients with GHD both before and after GH
replacement therapy and in age- and sex-matched healthy subjects.
Furthermore, we investigated the contribution of body fat distribution
to the interindividual variability in plasma GHBP responses to GH
replacement therapy in GHD patients.
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Subjects and Methods
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Twelve GHD adults, 7 men and 5 women, aged 25–60 yr, known to
have GHD for at least 2 yr (range, 3–20 yr), were included in the
study. GHD was defined as a peak plasma GH concentration of 5 µg/L or
less after arginine infusion. Twelve healthy sedentary adults (7 men
and 5 women), matched for age and sex, also participated in this study,
which was approved by the ethical committee of the University Hospital
of Utrecht. All subjects gave informed consent. Pertinent physical
characteristics of both groups are shown in Table 1
.
Secondary hypothyroidism (11 patients) was treated with levothyroxine
in a daily dose ranging from 75–200 µg (average dose, 134 µg);
secondary hypogonadism was treated with 80 mg testosterone undecanoate
twice a day orally or with testosterone esters (250 mg) every 3 weeks
im (6 men) and with cyclic estrogen (30 µg/day ethinyl estradiol) and
progesterone (150 µg/day levonorgestrel; 3 women); secondary adrenal
insufficiency (all patients) was treated with cortisone acetate in a
daily dose ranging from 10–37.5 mg (average dose, 28.3 mg). No
adjustments were made in replacement dose of any patient during GH
treatment. After the pretreatment measurements, all GHD patients were
treated during 6 months with daily sc injections of GH (Genotropin,
Pharmacia, Uppsala, Sweden). The initial dose was 0.041 mg/kg BW·week
during the first month, followed by 0.082 mg/kg·week.
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Table 1. Characteristics of the growth hormone deficient
patients (n = 12) before treatment and healthy subjects (n =
12)
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Blood samples were obtained after an overnight fast. We measured GHBP
levels by fast protein liquid chromatography gel chromatography after
the addition of a fixed amount (10 ng) of purified, monomeric
[125I]GH and different concentrations of radioinert GH
(0, 30, and 100 µg/L and 10 mg/L, the latter to determine aspecific
binding) to aliquots of serum, as described previously (18). The
coefficient of variation (CV) was 4%. Plasma GH concentrations were
determined using the RIA of the Oris Industry Co. (Gif-sur-Yvette,
France), which had a lower detection limit of 0.5 ± 0.04 µg/L
(1 µg/L = 2 mIU/L); the intra- and interassay CVs were 7.7% and
11%, respectively. GHBP levels were obtained by extrapolating the
maximal binding capacity from the Scatchard plot (18).
After separation of IGFs from IGF-binding proteins by Sep-Pak
C18 cartridge chromatography (19), IGF-I was measured by
RIA using the antiserum from Underwood and Van Wijk, distributed by the
NIDDK (20). At a concentration of 200 ng IGF-I/mL the in-between CV was
5.9%, and the within-assay CV was 7.9%.
Total body fat was assessed by bioelectrical impedance measurement,
using the tetrapolar BIA-101 analyzer (RJL-Systems, Detroit, MI).
Resistance and reactance were measured during application of an
alternating electric current of 800 µA at 50 kHz, with the electrodes
placed as described by Lukaski et al. (21).
The areas of AT were assessed by MRI scanning, performed with a 1.5-T
whole body scanner (Gyroscan S15, Philips Medical Systems, Best, The
Netherlands) using a multislice inversion-recovery sequence with a
300-ms inversion time, an 820-ms repetition time, and a 20-ms echo
time. This sequence highlights AT while effectively suppressing other
tissues (22). A transverse scan at the abdominal level, consisting of
three slices of 10 mm thickness with a gap of 2 mm, was taken halfway
between the lower rib margin and the iliac crest. A similar scan of the
hip was taken at the level of the great trochanter. A detailed
description of the analysis was published previously (17, 23). All
measurements were performed by the same observer and repeated in a
second session; the observer was blind to the subjects. The
intraobserver CV was 2.9% for the visceral AT areas in controls, and
2.0% and 3.7% in the GHD patients before and after GH replacement
therapy, respectively. For the sc abdominal AT areas, the intraobserver
CVs were 0.9%, 0.9%, and 1.7%, and for the sc AT areas at the hip
level, they were 0.8%, 0.9%, and 1.4%, respectively (17).
Statistical analysis
Student’s t test for unpaired samples was used to
assess differences between patients and healthy subjects. To evaluate
the effects of GH replacement therapy, Student’s t test for
paired samples was used. Plasma GHBP levels were correlated (Pearson
correlation coefficient) with BMI, visceral AT, and sc AT at the
abdominal and hip levels. Correlations of interest were evaluated with
linear regression analysis. Statistical significance was accepted for
P < 0.05. Results are expressed as the mean ±
SD.
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Results
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The characteristics of the GHD patients before treatment and those
of the healthy subjects are presented in Table 1
. Significant
differences between both groups were found for total body fat, plasma
GHBP and IGF-I, and all measured AT areas, with the exception of the sc
hip AT area. Regardless of the GH status of the subjects,
i.e. GHD, GHD plus replacement, or normal, the BMI and
visceral AT area were positively correlated to plasma GHBP (r =
0.70; P < 0.01 and r = 0.73; P <
0.01; Fig. 1, A and B, respectively), whereas sc AT
areas at the abdominal level tended to correlate positively with GHBP
levels, but did not reach significance (r = 0.44;
P = 0.07; Fig. 1C). The sc AT areas at the
hip level were not associated with plasma GHBP levels (r = 0.10;
P > 0.10; Fig. 1D).
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Figure 1. Relationship between BMI (A), visceral AT
area (B), sc AT area at the abdominal level (C), sc AT area at the hip
level (D), and circulating GHBP levels. Least squares regression lines
are depicted, regardless of the GH status of the subjects (n = 34
in stead of n = 36, because 2 posttreatment GHBP values are
missing).  , Male GHD patients;  , female GHD patients;  , male
controls;  , female controls.
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After 6 months of GH replacement therapy, mean plasma IGF-I was
significantly increased from 67 ± 36 to 226 ± 113 ng/mL
(P < 0.0001), which is in the range of the mean plasma
IGF-I of the healthy subjects (198 ± 36 ng/mL). The mean plasma
GHBP remained at about the same level (1259 ± 312 to 1266 ±
302 pmol/L; P = 0.31; n = 10 instead of n =
12, because 2 posttreatment GHBP values are missing). Interindividual
variability in plasma GHBP changes ranged from a decrease of 185 pmol/L
(-14% of the baseline value) to an increase of 230 pmol/L (+18% of
the baseline value). Body weight changed from 74.9 ± 14.7 to
75.5 ± 15.6 kg (P = 0.29), and BMI from 25.0
± 3.5 to 25.2 ± 3.8 kg/m2 (P =
0.31), whereas total body fat decreased from 18.7 ± 4.9 to
16.0 ± 5.3 kg (P = 0.004). Expressed as a
percentage of the baseline values the decreases in AT areas were 38.2%
for visceral AT (P = 0.002), 15.6% for sc abdominal AT
(P = 0.019), and 12.4% for sc hip AT area
(P = 0.006).
The pretreatment visceral AT area and the sc AT area at the abdominal
level were positively correlated with the changes in plasma GHBP after
GH replacement (r = 0.82; P < 0.01 and r =
0.75; P < 0.01; Fig. 2, A and B,
respectively), whereas the pretreatment sc AT area at the hip level was
not associated with the changes in plasma GHBP (r = 0.28;
P > 0.10; Fig. 2C). After GH replacement therapy,
changes in plasma GHBP and those in BMI were significantly negatively
correlated (r = -0.51; P = 0.02), whereas changes
in GHBP and those in visceral AT and the sc AT areas at the abdominal
or hip level were not correlated (r = 0.06, r = 0.35, and
r = 0.25, respectively).
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Discussion
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To our knowledge, this is the first study in which the AT
deposition in different parts of the body, as assessed by MRI scanning,
is associated with circulating high affinity GHBP levels in a group of
GHD patients and healthy subjects. MRI is a reliable and accurate
technique for determining adipose tissue volume (22, 23), whereas
circumference and skinfold thickness measurements have been found to be
inadequate to determine AT areas in GHD patients (17). Our study shows
that adult GHD patients have an increased visceral and sc abdominal AT
area compared to healthy subjects matched for age and sex. Six months
of GH replacement therapy reduced AT areas, with the most pronounced
reduction in visceral AT, as has been previously shown by Bengtsson
et al. (24) using computerized tomography. In addition, our
data show, regardless of the GH status of the subjects, significant
positive correlations between the BMI or the amount of visceral adipose
tissue and plasma GHBP, whereas sc adipose deposition at both the
abdominal and the hip level was not associated with plasma GHBP levels.
Our finding of an association of BMI with plasma GHBP (r = 0.70)
is consistent with previously reported studies (11, 12, 14, 15, 16).
Recently, Rasmussen et al. (13) showed that elevated GHBP
levels in obese subjects were restored to normal by diet-induced weight
loss. Next to the relationship between GHBP and BMI, the relationship
between plasma GHBP and body fat distribution might be of relevance for
the activity of the GH-IGF-I axis. In the study by Rasmussen et
al. (13), multiple stepwise regression analysis revealed that
changes in waist circumference and abdominal sagittal diameter during
weight loss were the major determinants of and accounted for 54% of
the fall in GHBP levels. In our study, linear regression analysis
revealed that 53% (R2 = 0.53) of the variability in plasma
GHBP could be explained by variation in visceral AT mass. Thus, 47% of
the variability in GHBP is not explained; however, it is conceivable
that other metabolic factors, such as insulin sensitivity, diet
composition, and thyroid hormone metabolism, may be operative. Indeed,
the positive association that we found between visceral fat and plasma
GHBP levels suggests that visceral fat may be involved in the
regulation of the plasma GHBP level. This reasoning is based on the
reported increased lipolytic rate in visceral fat (25, 26), which, via
increased plasma FFA levels, decreases GH release (27, 28), possibly
resulting in an increased GH sensitivity and up-regulation of the GH
receptor. Based on our results and the assumption that GHBP is derived
from proteolytic cleavage of the extracellular domain of the GH
receptor (14, 29), it is tempting to speculate that an increase in
plasma GHBP is a consequence of up-regulation of the GH
receptor-binding sites in hyposomatotropic states such as GHD and
obesity.
Recent data concerning GH replacement therapy in GHD patients showed an
interindividual variability in the GHBP response (30, 31, 32, 33). In this
study we also found a variable response of plasma GHBP, ranging from
-14% to +18% of the baseline value. Notwithstanding the small number
of subjects in our study, pretreatment abdominal fat mass
(i.e. visceral and sc AT) and the changes in plasma GHBP
levels after GH replacement therapy were significantly positively
correlated (r = 0.82; P < 0.01 and r = 0.75;
P < 0.01), whereas no significant correlations were
observed between changes in these AT areas and changes in GHBP. Thus,
it seems that the pretreatment amount of abdominal fat mass partly
determines the GHBP changes induced by GH replacement therapy.
Therefore, it is conceivable that a low pretreatment abdominal fat mass
shifts the dose-response curve of GH replacement therapy to the left,
i.e. that a lower dose of GH is needed to be effective.
However, this does not provide a satisfactory explanation for why no
correlations between the changes in AT areas and the changes in GHBP
after GH therapy were found. It could be argued, however, that in a
static condition concerning body fat (pretreatment), central fat mass
and GHBP are significantly correlated, but that this correlation
disappears in a dynamic state (GH treatment period), in which not only
central fat mass and GHBP activity change, but other factors, such as
insulin activity and catecholamines, change as well. Our observation
that not only the visceral fat mass, but also the sc abdominal fat
mass, albeit more weakly, were associated with changes in plasma GHBP,
suggests that the sc abdominal fat mass is not only an energy depot,
but may be metabolic active.
Taken together, the data presented in this study clearly indicate a
significant role of abdominal fat mass in circulating high affinity
GHBP levels. If circulating GHBP levels are indicative of the GH
receptor status of target tissues, an increase in abdominal fat may
induce an increased density of GH receptor-binding sites, compensating
for the decreased GH secretion in hyposomatotropic states.
Received July 29, 1996.
Revised November 20, 1996.
Accepted December 5, 1996.
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Top
Abstract
Introduction
