Association of Retinol-Binding Protein-4 (RBP4) with Lipid
Parameters in Obese Women
Montserrat Broch & José Manuel Gómez & Ma Teresa Auguet & Nuria Vilarrasa &
Rosa Pastor & Iñaki Elio & Montserrat Olona & Antonio García-España &
Published online: 11 June 2010
# Springer Science+Business Media, LLC 2010
Background Although the adipokine retinol-binding
protein-4 (RBP4) has been implicated in the development
of obesity-related insulin resistance, its role in human
obesity is still unclear. Our objectives were to find out the
effect on RBP4 systemic levels of a weight loss induced by
gastric bypass surgery and to analyze RBP4 relationships
with insulin resistance, parameters of body composition,
lipid metabolism, and inflammation.
Methods Sixty-three obese women were analyzed before
and 12 months after surgery of systemic concentrations of
RBP4, fasting glucose, insulin, lipid profile molecules, and
inflammation-related proteins (C-reactive protein, tumor
necrosis factor-alpha receptors 1 and 2, interleukin-18, and
adiponectin), and waist and hip circumference measure-
ments, body mass index calculation, and insulin resistance
index by homeostasis model assessment were also made.
Results We found that RBP4 levels were lower after weight
reduction by gastric bypass surgery (p<0.0001). We found
RBP4 associated with triglycerides before (β=0.37, p=0.02)
and after surgery (β=0.59, p<0.0001) and negatively with
weight loss after surgery (β=−0.37, p=0.003). When
expressed as a percentage of change, the decrease of RBP4
was related to the reduction in the levels of triglycerides and
with the increase in HDL-cholesterol (β=0.73, p=0.02 and
β=0.62, p=0.04, respectively). Others parameters analyzed,
including inflammatory markers, were not related to RBP4.
Conclusions This study shows that, in obese women and
after a substantial weight loss due to bariatric surgery,
RBP4 was related to weight status and lipid parameters
rather than to insulin sensitivity or inflammatory markers.
Keywords Obesity.Gastric bypass surgery.Weight
Obesity is considered an important risk factor for the
development of many metabolic disorders such as low-grade
M. Broch:M. T. Auguet:C. Richart
CIBER (CB06/03) Fisiopatologia de la Obesidad y Nutrición,
Instituto de Salud Carlos III,
J. M. Gómez:N. Vilarrasa:I. Elio
Endocrinology and Diabetes Unit,
Hospital Universitari de Bellvitge,
M. T. Auguet:C. Richart
Internal Medicine, Hospital Universitari de Tarragona Joan XXIII,
Hospital Universitari de Tarragona Joan XXIII,
Epidemiology and Statistics,
Hospital Universitari de Tarragona Joan XXIII,
M. Broch:M. T. Auguet:A. García-España:C. Richart
Institut d’Investigació Sanitaria Pere Virgili,
Universitat Rovira i Virgili,
M. Broch (*)
Research Unit, Hospital Universitari de Tarragona Joan XXIII,
C/ Dr. Mallafré Guasch s/n,
43007 Tarragona, Spain
OBES SURG (2010) 20:1258–1264
chronic inflammation, insulin resistance, dyslipidemia,
arterial hypertension, and atherosclerosis . Variations in
the systemic concentrations of some peptides called adipo-
kines, which are secreted by the adipose tissue, have been
implicated in the development of obesity and its related
metabolic alterations .
Retinol-binding protein-4 (RBP4), the only known carrier
of vitamin A in the blood, is synthesized in several tissues,
primarily in the liver and alsointhe adipose tissue (AT) [3, 4].
After the finding of elevated RBP4 protein levels in the AT
and in the circulatory system in an adipocyte-specific
glucose transporter 4 knockout mouse (Glut4−/−) model, it
was proposed that RBP4 could act as an adipokine linking
adipocyte glucose metabolism with systemic insulin sensi-
tivity . However, in humans, this role is still unclear since
a correlation has not always been found between systemic
RBP4 and insulin resistance indices (homeostasis model
assessment of insulin index (HOMA-IRI), euglycemic
clamp) and/or adiposity measurements such as waist-to-hip
ratio (WHR), body mass index (BMI), and fat mass [5–7].
Furthermore, RBP4 has been found to be associated instead
with blood pressure, systemic levels of triglycerides (TGL),
small low-density lipoproteins (sdLDL), C-reactive protein
(CRP), and interleukin (IL)-6 [8, 9], suggesting that the
relationship of RBP4 with insulin resistance (IR) in humans
is still not fully understood.
When RBP4 was previously analyzed in obesity after
weight reduction, which is always followed by an improve-
ment in obesity-related metabolic disorders, systemic
concentration of RBP4 was lower in some studies
[10–16], but not in others [17, 18]. Moreover, the
improvement in the insulin sensitivity indices that occurs
after a weight loss was found positively associated with the
reduction in systemic RBP4 levels in only some of the
above mentioned studies [10, 12, 15, 16].
As an extension of our previous analysis of RBP4 in
human obesity  and since the results regarding RBP4
behavior after a weight reduction as well as the relationship
of RBP4 with IR and obesity parameters were still unclear,
we measured the RBP4 circulating levels in obese women,
before and after a considerable (35%) weight reduction due
to a gastric bypass surgery. We hypothesize that systemic
levels of RBP4 are conditional on a big weight reduction and
they are associated with a change in metabolic parameters.
Sixty-three women aged 45.0±9.3 years with a BMI of
49.7±8.0 kg/m2(range 36.5–70.4 kg/m2) were recruited
from the Endocrinology Service of Bellvitge Hospital
(Barcelona, Spain) from patients scheduled for gastric
bypass surgery, which was performed according to a
modification of the method described by Capella et al. .
Subjects with the following conditions were excluded
from the study: type 2 diabetes mellitus (DM2) with insulin
or hypoglycemic agent treatment, myocardial infarction
during the last 6 months, recent infection, history of cancer,
Cushing’s syndrome, thyroid dysfunction, or other major
endocrine disorders. Patients suffering from eating disor-
ders or major psychiatric illness, or who consumed alcohol
(more than 60 g/day) or smoked (more than 12 cigarettes/
day), were also excluded.
Medical treatment with hypolipemic agents in all
subjects and hormone therapy in menopausal women was
suspended 3 weeks before gastric bypass surgery. At this
point, all patients were instructed to follow a very low
caloric diet (800 kcal) to ensure weight loss after surgery
and to minimize surgical risk. Before and after surgery,
patients were closely monitored and none experienced
worsening in their metabolic control.
Pre- and postoperative anthropometrical measurements
and collection of morning fasting venous blood samples
were performed before and 12 months after the surgical
intervention. Type 2 diabetes mellitus was diagnosed using
the World Health Organization criteria  before surgery.
Twelve months after, patients with plasma glucose levels
<126 mg/dl with normal hemoglobin A1c (HbA1c) values
were considered to be nondiabetic.
All women were of Caucasian origin. This study was
approved by the hospital’s ethical committee. All subjects
gave their informed consent to participate in the study.
All examinations were performed by the same person.
Body height and weight were measured with the patient
standing in light clothes, without shoes. BMI was
calculated as body weight divided by height squared
(kilogram per square meter). Each of the subject’s waist
was measured with a soft measuring tape midway between
the lowest rib and the iliac crest, and the hip circumference
was measured at the widest part of the gluteal region.
Blood samples were obtained from the subjects after an
overnight fast. Plasma and serum samples were stored at −80°
C until the analytical measurements were performed, except
for glucose, which was determined immediately after the
blood was drawn. Glucose was measured in the serum using
the glucose oxidase method. HbA1c was measured using the
chromatographic method (Glico Hb Quick Column Proce-
dure, Helena laboratories, Beaumont, TX, USA). The total
OBES SURG (2010) 20:1258–12641259
serum cholesterol was measured through the reaction of
cholesterol esterase/cholesterol oxidase/peroxidase. High-
density lipoprotein cholesterol was quantified after precipita-
tion with polyethylene glycol at room temperature. Serum
triglycerides were measured through the reaction of glycerol-
phosphatase-oxidase and peroxidase. All these parameters
were measured using an autoanalyzer (Bayer, Terrytown, NY,
USA). Low-density lipoprotein cholesterol was calculated
with the Friedewald equation if the serum triglyceride levels
were below 400 mg/dl . Fasting insulin was measured by
monoclonal immunoradiometric assay with the basic over-
night procedure (Medgenix Diagnostics, Fleunes, Belgium),
which has a sensitivity of 1.2 µU/ml. The intra- and
interassays were <9.3% and <10%, respectively.
The degree of insulin resistance was measured by HOMA-
IRI with the equation HOMA-IRI=insulin (µU/ml)×glucose
(mmol/l)/22.5. This index fairly correlates with the insulin
sensitivity index calculated from frequently sampled intrave-
nous glucose tolerance test minimal model analysis . The
reference range for HOMA index that was validated by our
previous values found in healthy volunteers was 2.16±1.3
RBP4inserum samples was measuredusingnephelometry
(Dade Behring Inc., Marburg, Germany). The sensitivity of
the method was 0.1 ng/dl and the intra- and interassays were
<4.3% and <4.4%, respectively. CRP levels were determined
in serum by nephelometry with the high sensitivity CRP kit
(Dade Behring). The sensitivity was 0.175 mg/l and the intra-
and interassays were <4.4% and <5.7%, respectively. Soluble
tumor necrosis factor receptor 1 and 2 (sTNFR1–R2) were
determined in plasma by solid phase enzyme immunoassay
with amplified reactivity (BioSource Europe SA, Nivelles,
Belgium). The detection limit was 50 pg/ml for sTNFR1 and
0.1 ng/ml for sTNFR2, and the intra- and interassays were
≤7% and ≤9% for sTNFR1 and <6.5% and <8.9% for
sTNFR2, respectively. The sTNFR1 assay does not cross-
react with sTNFR2. TNF-α does not interfere with the assay.
Plasma IL-18 concentrations were measured using human
IL-18 sandwich enzyme-linked immunosorbent assay (Med-
ical & Biological Laboratories Co Ltd, Nagoya, Japan) with
a sensitivity of 12.5 pg/ml. The intra- and interassay
coefficients of variation were 10.8% and 10.7%, respectively.
Plasma adiponectin levels were measured using the
human adiponectin RIA kit (Linco Research, St. Charles,
MO, USA) with a detection limit of 0.001 µg/ml. The intra-
and interassay coefficients of variation were 8% and 12%,
respectively. Samples were diluted 1:500. All samples in all
determinations were measured in duplicate.
A statistical analysis was performed using the SPSS/PC+
statistical package v.13 for Windows (Chicago, IL, USA).
Variables with skewed distribution assessed using the
Kolmogorov–Smirnov test of normality were log-
transformed before the analysis. The differences between
the variables before and after weight loss were analyzed
using a two-tailed paired t test. Pearson’s correlation
coefficient and linear regression analysis were used in
order to explore the relationships between two variables.
The validity of the regression model and its assumptions
were assessed with the plot of residuals vs. predicted.
Multivariable linear regression analysis by backward
method was performed to identify independent factors
affecting RBP4 systemic concentrations, choosing the
model with the best goodness-of-fit. Additionally, a
statistical analysis was done with the percentage of change
in adiposity, metabolic variables and, RBP4 concentrations.
The percentage of change was calculated as follows:
(before weight reduction − after weight reduction)×100/
before weight reduction. In all cases, the level of
significance chosen was p≤0.05.
Table 1 shows the anthropometric and metabolic character-
istics of the study subjects before and 12 months after
gastric bypass surgery. On average, these 63 subjects were
middle-aged, morbidly obese, dyslipidemic (with elevated
triglyceride and total cholesterol levels), and insulin
resistant. Of the 24 subjects with type 2 diabetes before
gastric bypass surgery, only 2 remained with characteristics
of type 2 diabetes 12 months after surgery. The RBP4 basal
levels of these 24 diabetic patients tend to be statistically
higher than the levels of the 39 subjects without diabetes
(3.32±0.9 vs. 3.0±0.8 mg/dl, respectively, p=0.08).
The systemic concentrations of RBP4 were significantly
reduced after surgery in all subjects (Table 1). On the other
hand, as expected after bariatric surgery, the patients had a
significant reduction of body weight, BMI, and WHR, as
well as a significant improvement in the initial glycemia,
insulinemia, and insulin sensitivity. An improvement in the
lipid profile was also observed: the levels of total cholesterol,
triglycerides, and LDL-cholesterol were significantly re-
duced, and HDL-cholesterol levels were significantly in-
creased. The systemic levels of the inflammatory markers
analyzed were also significantly diminished (Table 1).
Relationships Between RBP4 and Anthropometric and
Metabolic Parameters Before and After Bariatric Surgery
When we analyzed the relationships of RBP4 before the
the concentrations of RBP4 were positively correlated with
age (r=0.29; p=0.03), fasting glucose (r=0.37; p=0.006),
1260 OBES SURG (2010) 20:1258–1264
glycosylated hemoglobin (r=0.40, p=0.009), and triglycer-
ide levels (r=0.37; p=0.01) and showed a tendency to be
associated with cholesterol levels (r=0.26; p=0.06). In a
model of multiple regression analysis in which we included
all the parameters above mentioned (with HbA1c or fasting
glucose), only the triglyceride concentrations appeared as an
independent factor related to RBP4 basal concentrations
(β=0.37, p=0.02), adjusted R-square=12%.
After bariatric surgery, in the bivariate analysis, the RBP4
concentrations correlated with fasting insulin levels (r=0.30,
p=0.04) and the measure of insulin resistance HOMA-IR
(r=0.30, p=0.05), total cholesterol levels (r=0.38; p=0.009),
triglyceride levels (r=0.55; p<0.0001), and LDL-cholesterol
concentrations (r=0.20; p=0.05), and inversely with weight
loss (r=−0.36; p=0.02). After a multiple linear regression
analysis with the above variables, triglyceride levels and
weight loss remained significantly associated with RBP4
concentrations. In these associations, triglyceride levels were
the parameter strongly related to RBP4 (weight loss:
β=−0.37, p=0.003; TGL levels: β=0.60, p<0.0001),
Relationship Between the Percentage of Change in RBP4
and Those in Triglycerides and HDL-Cholesterol
The patients, after the bariatric surgery intervention, had a
mean weight loss of 41.2±15 kg and a 19.9% decrease in
the RBP4 systemic concentration (Table 1). We calculated
the percentage of change after 12 months of surgery in all
variables (described in “Statistical Analysis” section)
(Table 1). The percentage of change in RBP4 associated
significantly with the percentage of change in fasting
glucose (r=0.46; p=0.004), HbA1c (r=0.46; p=0.02), and
triglycerides (r=0.34; p=0.05) and showed a tendency to
be associated with percentage of change in HDL-
cholesterol levels (r=0.33; p=0.09).
To confirm these associations, we performed multi-
variable regression analysis with a model including the
Table 1 Anthropometric and metabolic parameters of obese women before and 12 months after gastric bypass surgery
N=63 women Before surgery (baseline)After surgery (12months)p Change (%)a
Body composition parameters
Body weight (kg)
Weight loss (kg)
Fasting glucose (mM)
Fasting insulin (µU/ml)
HOMA-IR (µU/ml × mM)
Total cholesterol (mM)
C-reactive protein (mg/dl)
Data are mean ± SD. Differences between groups were analyzed by two-tailed paired Student’s t test. Change (%) is: (before weight reduction −
after weight reduction)×100/before weight reduction
BMI body mass index, WHR waist-to-hip ratio, HbA1c glycosylated hemoglobin, HOMA-IR homeostasis model assessment of insulin resistance,
RBP4 retinol-binding protein-4, sTNFR1 and R2 soluble tumor necrosis factor-alpha receptors 1 and 2
*p≤0.05, statistical differences between the groups
aNegative value in change (%) indicates that measure after 12 months of intervention was higher than the basal value, indicated as (↑)
OBES SURG (2010) 20:1258–12641261
above parameters with fasting glucose or HbA1c in
separate models (all parameters in percentage of change).
We found that both the percentage of change in
triglycerides and in HDL-cholesterol concentrations were
independent factors associated with the percentage of
change in RBP4 concentrations, β=0.73, p=0.02 and β=
0.62, p=0.04, respectively, adjusted R-square=20%.
Relationships of RBP4 with Proinflammatory Adipokines
and with Adiponectin
After the bariatric surgery, the inflammatory markers
analyzed behaved as expected: the systemic levels of
CRP, TNFR2-soluble fraction, and IL-18 were significantly
reduced by 71.5%, 17.1%, and 16.4%, respectively. The
only exception was TNFR1-soluble fraction that remained
similar (Table 1). On the other hand, the concentration of
the antiinflammatory adipokine adiponectin increased sig-
nificantly (−114.2%) (Table 1). In these conditions, the
RBP4 levels before and after bariatric surgery and the
magnitude of the percentage of change in RBP4 systemic
levels were not related to these inflammatory parameters
(all, r≤0.19 and p≥0.23).
In this study, we show that RBP4 systemic levels in obese
women were significantly lower after a substantial weight
reduction due to gastric bypass surgery. We also show an
association between RBP4 concentration and the
percentage of change mainly with lipid parameters.
Lower RBP4 levels after surgery are in agreement
with the results from studies of morbidly obese patients
after gastric banding surgery [10, 11] and results from
studies of obese subjects after weight reduction programs
such as diet, exercise, and pharmaceutical interventions
[12, 16]. In other studies, however, RBP4 levels were
unchanged after weight reduction [17, 18]. The size of
body weight reduction may partly explain these different
results: the weight reductions in the latter two studies were
only 5% and 7%, respectively, compared to 34.7% for the
subjects in our study and an average of 15.9% for the
subjects in [10–15].
As previously reported in subjects incurring a big
weight loss , our patients also showed a significant
improvement in glucose metabolism, insulin resistance,
and lipid profile. Although RBP4 has been associated with
insulin resistance [3, 4, 25, 26] and in this study we
describe associations with HOMA index and fasting
insulin concentrations, we do not found any clear
relationship between this adipokine and the above param-
eters after controlling for possible confounding factors. As
we expected, serum adiponectin levels, which are known
to be decreased with fat accumulation and insulin
resistance , correlated significantly and inversely with
HOMA-IR and fasting insulin (and positively with HDL-
cholesterol levels) (data not shown). Adiponectin levels
showed no correlation with RBP4. These data may
suggest that, for the conditions in our study, serum
adiponectin, rather than RBP4, is more closely associated
with insulin resistance, and thus, RBP4 is not a marker of
For the relation of RBP4 and insulin resistance,
conflicting results have been reported in studies on humans
[3–11, 25, 26], including a variety of factors that may affect
not to obtain similar results, as methodological differences
in the determination of RBP4 concentrations and IR
parameters, sample size, or diabetic patient’s characteristics
[28, 29]. But recently, the contribution of a genetic factor
and age has been proposed. Thus, genetic variations may
determine RBP4 levels  and contribute to insulin
resistance susceptibility [31–33], although the direction of
the effect was not uniform. Moreover, a recent twin study
suggests that the influence of environmental vs. genetic
factors in the regulation of plasma RBP4 increases with age
and that the association of RBP4 with insulin resistance is
secondary and noncausal . These two components add
complexity to the relationship between RBP4 and RI and
may offer an explanation why this association in obese
women as well as in other subjects reported so far are
We found that RBP4 correlated mainly with systemic
lipoprotein concentrations. Expressed as a percentage of
change, the reduction in RBP4 levels associates with the
reduction in TGL levels and the increase in HDL-
cholesterol levels, and the TGL concentrations explain
12% RBP4 concentrations before surgery and 45% RBP4
concentrations (together with weight loss) after surgery.
TGL levels were the strongest variable to explain RBP4 in
all the multiple regression analyses. Our finding of an
association between RBP4 and TGL is in agreement with
the study of Lee et al.  of healthy subjects submitted to
a weight reduction program.
In studies in which RBP4 was also assessed after
weight reduction, the lipid profile was either not
considered [12, 17, 18] or only partially evaluated [12,
13], or the differences between the lipid profile before and
after surgery were not statistically different in all the lipid
parameters [10, 14–16]. Also, in all these studies, weight
loss was much lower than in our subjects. In one study
with a similar weight reduction in which the lipid profile
was assessed, while there was a significant improvement
in all lipid parameters, RBP4 was not related to the lipid
profile, perhaps because the group of patients was too
small (n=21) .
1262 OBES SURG (2010) 20:1258–1264
A relationship between RBP4 and lipid parameters has
been suggested by Ng et al. in male patients with metabolic
syndrome since weight loss after a low fat diet led to an
increase in LDL catabolism that was inversely correlated with
the decrease in RBP4 systemic concentrations and a decrease
in HDL catabolism that correlated with RBP4 levels, even
after obesity parameters were controlled . In addition,
RBP4 was associated with TGL and with very low-density
lipoprotein (VLDL)-cholesterol levels in healthy subjects,
DM2 patients, and subjects with coronary artery disease, but
not with insulin resistance . Although these reports and
our present study reveal a possible involvement of the RBP4
with lipid metabolism, the physiological and pathological
significance of these findings remains unresolved. Neither is
known if RBP4 could act alone or bound to retinol in these
pathways. RBP4 is the sole transporter for retinol in the
circulation, and retinoids are known to increase hepatic
production of VLDL , so it has been suggested that
RBP4 may alter the steady-state plasma VLDL by
influencing its hepatic production . Since triglycerides
are the main component of VLDL lipoproteins, the indepen-
dent association between TGL with RBP4 concentrations
that we found could be the reflection of the relationship
between RBP4 with hepatic VLDL metabolism. In addition,
the RBP4 systemic concentrations have been positively
related to the activity of hepatic lipase , a lipolitic enzyme
whose activity has been associated with the levels of HDL
metabolism , suggesting the possible link between RBP4
and HDL lipoproteins.
On the other hand, again, it is possible that in the
independent association that we found with lipid parame-
ters, there was a contribution of genetic factors since recent
studies suggest an important genetic component in these
associations [37, 38].
The main tissues related to lipid metabolism are adipose
tissue and the liver. Although both express RBP4, we found
no association between RBP4 and adiposity measurements.
Thisisinagreement withthe absence ofa correlationbetween
RBP4 systemic levels and its expression in subcutaneous
adipose tissue in lean and obese subjects found by us and by
other authors [17, 39]. It has also been suggested that
hepatocytes contribute to a large proportion of systemic
RBP4 protein concentration in humans as what happens in
rodents, where the liver is the key organ involved in
regulating circulating RBP4 levels [40–42]. Interestingly,
RBP4 systemic levels have been directly related to liver fat
content in humans  and positively related to the activity of
hepatic lipase . These observations suggest that the liver is
the main tissue responsible for regulating RBP4 systemic
concentrations also in obesity.
Another finding in this work is that we found no
relationship between RBP4 and inflammatory parameters
(CRP, IL-18, sTNFR1, R2 and adiponectin). This is in
agreement with our previous finding in nonmorbidly obese
patients, where RBP4 was found to be unrelated to CRP or
adiponectin . The lack of an association between RBP4
and circulating levels of inflammatory parameters does not
allow any relationship to be established between this
adipokine and the low-grade of inflammation measured in
the population studied. To our knowledge, this relationship
has not been assessed in morbidly obese adults after
massive weight reduction and futures studies are needed
to confirm our results.
In conclusion, our study shows that RBP4 systemic
levels are lower after a substantial weight reduction in
women undergoing gastric bypass surgery. RBP4 was
associated with TGL and HDL-cholesterol levels but not
with insulin sensitivity or measurements of obesity. These
findings suggest that RBP4 cannot be construed as a marker
of insulin resistance in our studied conditions but may
indicate a role for this protein in lipid metabolisms. The
mechanism and the sites where RBP4 may be involved are
of interest for future studies.
study. This work was supported by research grants SAF2005-00413
and SAF2008-02278 (both to C.R.) from the Spanish Ministry of
Science and Innovation (co-financed by FEDER) and by the
We thank all the women who participated in the
Conflict of interest statement
no commercial conflicts of interest.
All the authors declare that they have
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