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Endocrinology and Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom
Address all correspondence and requests for reprints to: Dr. Harpal S. Randeva, Endocrinology and Metabolism Group, Clinical Sciences Research Institute, Warwick Medical School, University of Warwick, Coventry CV4 7AL, United Kingdom. E-mail: harpal.randeva{at}warwick.ac.uk.
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Abstract |
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Objectives: mRNA expression of RBP4 from sc and omental (om) adipose tissue and sc adipocytes in overweight PCOS women were compared with matched controls; RBP4 protein in adipose tissue and serum RBP4 levels were also assessed. Additionally, we studied the effects of testosterone, 17ß-estradiol, androstenedione, and dehydroepiandrosterone sulfate on RBP4 expression in adipose tissue explants.
Design: Real-time RT-PCR and Western blotting were used to assess the relative mRNA and protein expression of RBP4. Biochemical measurements were also performed.
Results: Compared with controls, there was significant up-regulation of RBP4 mRNA in sc (P < 0.05) and om (P < 0.01) adipose tissue as well as isolated sc adipocytes (P < 0.01) of PCOS women. In addition to elevated serum RBP4 levels in PCOS women (P < 0.05), RBP4 protein levels were significantly greater in sc and om adipose tissue of PCOS women (P < 0.05 and P < 0.05, respectively). Furthermore, in human sc and om adipose tissue explants, 17ß-estradiol significantly increased RBP4 mRNA expression, protein levels, and secretion into the culture media (P < 0.05).
Conclusions: The precise reason for elevated levels of RBP4 in overweight PCOS women is unknown, but it appears that 17ß-estradiol may play a role in their regulation in adipose tissue.
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Introduction |
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The metabolic syndrome is associated with excessive accumulation of central body fat. Besides its role in energy storage, adipose tissue produces several hormones and cytokines that have wide-ranging effects on carbohydrate and lipid metabolism. They appear to play an important role in the pathogenesis of IR, diabetes, and atherosclerosis (4). Studies of adipocyte-specific glucose transporter 4 (GLUT4) knockout mice recognized retinol-binding protein 4 (RBP4) as an adipokine that contributes to IR in obesity and T2DM by inducing the expression of hepatic gluconeogenic enzymes and impairing insulin signaling in muscle (5). Additional studies revealed elevated serum/plasma RBP4 levels in humans with obesity, impaired glucose tolerance, and T2DM (5, 6). More recently, studies on isolated human sc primary adipocytes have confirmed RBP4 as a human adipokine (7).
Because PCOS is a prodiabetic state with a higher prevalence of obesity (1, 2), we measured serum RBP4 levels and studied the mRNA expression and protein levels of RBP4 in sc and omental (om) adipose tissue depots in these women against age, body mass index (BMI), and waist-to-hip ratio (WHR) matched controls. With PCOS being a state of altered gonadal and adrenal steroids, we also assessed the effects of these hormones on RBP4 mRNA expression and protein levels in human sc and om adipose tissue explants.
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Subjects and Methods |
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All PCOS patients met all three criteria of the revised 2003 Rotterdam European Society of Human Reproduction/American Society for Reproductive Medicine PCOS Consensus Workshop Group diagnostic criteria (8). Furthermore, all subjects in the control arm had normal findings on pelvic ultrasonic scan, regular periods, and no hirsutism/acne. No women were amenorrheic. Exclusion criteria for the study included age older than 40 yr, known cardiovascular disease, thyroid disease, neoplasms, current smoking, diabetes mellitus, hypertension (blood pressure, >140/90 mm Hg), and renal impairment (serum creatinine, >120 µmol/liter). None of these women were on any medications for at least 6 months before the study, including oral contraceptives, glucocorticoids, ovulation induction agents, antidiabetic and antiobesity drugs, estrogenic, and antiandrogenic or antihypertensive medication. Also, the presence of other endocrinopathies were ruled out by measuring basal serum 17-hydroxyprogesterone and prolactin and by measuring 0800–0900 h cortisol after 1.0 mg (2300 h) overnight dexamethasone suppression (value < 30 nmol/liter was considered to rule out Cushing’s syndrome). All subjects suppressed cortisol less than 30 nmol/liter.
After an overnight fast, blood samples and sc and om adipose tissue were obtained (0800–1000 h) from adult female patients undergoing elective surgery for infertility investigation. Subcutaneous biopsies were obtained from the same site, i.e. from a 3-cm horizontal midline incision approximately 3 cm above the symphysis pubis. All samples were obtained during the early follicular phase (d 2–4 from the first day of spontaneous bleeding episode). Serum/plasma was immediately aliquoted on ice and stored at –80 C. To study corresponding adipose tissue and adipocytes, the same fat pad was divided equally into two halves. Each half was either immediately frozen in liquid nitrogen and stored at –80 C or placed into a sterile container containing Medium 199 (Sigma, Gillingham, UK) for primary adipocyte isolation and adipose tissue culture. The control group had no discernible cause for infertility (unexplained infertility). Subjects underwent either a hysterocontrast sonography or a laparoscopy to assess fallopian tube(s) patency. All patients underwent anthropometric measurements, i.e. weight, height, and WHR. Equal numbers of women were recruited (n = 10 in each group): one consisted of PCOS women and the other, normal controls, had unexplained infertility and normal hormonal profiles (Table 1
). The Local Research Ethics Committee approved the study, and all patients involved gave their informed consent, in accordance with the guidelines in The Declaration of Helsinki 2000.
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Assays for glucose, insulin, LH, FSH, 17ß-estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEA-S), and SHBG were performed using an automated analyzer (Abbott Architect; Abbott Laboratories, Abbott Park, IL). The estimate of IR by homeostasis model assessment (HOMA) score was calculated as Io x Go/22.5, where Io is the fasting insulin and Go is the fasting glucose, as described by Matthews et al. (9).
RBP4 levels in serum and culture media from human om adipose tissue explants were measured using a commercially available enzyme immunoassay (EIA) (EIA kit; Phoenix Pharmaceuticals, Belmont, CA), according to the protocol of the manufacturer, with an intraassay coefficient of variation of less than 6%.
Isolation of primary adipocytes
Primary adipocytes were isolated by a method modified from that of Rodbell and Gliemann et al. (10, 11). Fat samples were washed with large volumes of PBS, were then meticulously cleaned of obvious blood vessels, connective tissue, and skin, and were then chopped with sterile scissors. The cleaned samples were washed again with saline, and the floating, clean fat was recovered by centrifugation. Adipocytes were isolated by collagenase digest [Hanks’ balanced salt solution containing 3 mg/ml collagenase (type II) and 1.5% BSA] in a shaking water bath at 37 C for up to 60 min. Mature adipocytes were separated from the stromal vascular cells through an inert oil, bis[3,5,5 trimethylhexyl]phthalate (Fluka Chemicals, Gillingham, UK). Total RNA extraction and cDNA synthesis from isolated adipocytes were performed immediately as described below.
Primary explant culture
Adipose tissue organ explants were cultured using methods described by Fried and Moustaid-Moussa (12). Briefly, 1–3 g adipose tissue was minced into 5–10 mg [
1 mm (Ref. 3)] fragments, washed with a 230 µm mesh (filter no. 60; Sigma), and rinsed with sterile PBS warmed to 37 C. Samples were then transferred to six-well plates containing 3 ml of Media 199 (Invitrogen, Paisley, UK) supplemented with 50 µg/ml gentamicin and 1% fetal bovine serum and cultured for 4 and 24 h with or without the addition of 100 nM testosterone, 17ß-estradiol, androstenedione, DHEA-S, and insulin in a 37 C incubator under an atmosphere of 5% CO2/95% air.
Total RNA extraction and cDNA synthesis
Total RNA was extracted from whole adipose tissue samples and isolated adipocytes using Qiagen RNeasy Lipid Tissue Mini kit according to the guidelines of the manufacturer (Qiagen, Crawley, UK). First-strand cDNA synthesis was performed using Moloney murine leukemia virus reverse transcriptase and random hexamers as primers.
RT-PCR
Quantitative PCR of RBP4 and GLUT4 were performed on a Roche Light Cycler system (Roche Molecular Biochemicals, Mannheim, Germany) (13) (supplemental data, published on The Endocrine Society’s Journals Online web site at http://jcem.endojournals.org). The sequences of the sense and antisense primers used were as follows: RBP4 (118 bp), 5'-TACTCCTGCCGCCTCCTGAA-3' and 5'-CCTGCCGCTGCCTTACAATC-3'; GLUT4 (106 bp), 5'-CGACCAGCATCTTCGAGACA-3' and 5'-TCCACCAACAACACCGAGAC-3'; ß-actin (216 bp), 5'-AAGAGAGGCATCCTCACCCT-3' and 5'-TACATGGCTGGGGTCTTGAA-3'; vimentin (170 bp), 5'-GAGAACTTTGCCGTTGAAGC-3' and 5'-TCCAGCAGCTTCCTGTAGGT-3'; von Willebrand factor (174 bp), 5'-TGCTGACACCAGAAAAGTGC-3' and 5'-AGTCCCCAATGGACTCACAG-3'; CD45 (194 bp), 5'-AGGAGAGTGAATGCCTTCAG-3' and 5'-GCCTCTACTTGAACCATCAG-3'; and CD14 (173 bp), 5'-CGCAACACAGGAATGGAGAC-3' and 5'-CCAGCGAACGACAGATTGAG-3'. PCR products were then sequenced in an automated DNA sequencer, confirming the identity of our products (supplemental data).
Western blotting
Protein lysates were prepared by homogenizing adipose tissue in radioimmunoprecipitation lysis buffer (Upstate Biotechnology, Lake Placid, NY) according to the instructions of the manufacturer. Equal amounts of Laemmli buffer [5 M urea, 0.17 M SDS, 0.4 M dithiothreitol, and 50 mM Tris-HCl (pH 8.0)] were added, mixed, and placed in a boiling water bath for 5 min. Lysates were allowed to cool at room temperature. The proteins (35 µg/lane) were separated by SDS-PAGE (8% resolving gel) and transferred to polyvinylidene difluoride (PVDF) membranes at 100 V for 1 h in a transfer buffer containing 20 mM Tris, 150 mM glycine, and 20% methanol. PVDF membranes were blocked in Tris-buffered saline containing 0.1% Tween 20 and 5% BSA for 1 h. The PVDF membranes were incubated with primary rabbit antihuman antibody for RBP4 (1:2000; ALPCO Diagnostics, Salem, NH) (RBP4 antibody was made against full-length recombinant RBP4 expressed in Escherichia coli), primary rabbit antihuman antibody for GLUT4 (1:1000; Abcam, Cambridge, Cambridgeshire, UK), or primary rabbit antihuman antibody for ß-actin (1:1000 Cell Signaling Technology, Beverly, MA) overnight at 4 C. The membranes were washed thoroughly for 60 min with Tris-buffered saline-0.1% Tween 20 before incubation with the secondary antirabbit horseradish peroxidase-conjugated Ig (1:2000; DakoCytomation, Ely, Cambridgeshire, UK) for 1 h at room temperature. Antibody complexes were visualized using chemiluminescence (ECL+; GE Healthcare, Little Chalfont, Buckinghamshire, UK). Human RBP4 peptide (Phoenix Pharmaceuticals) (full-length recombinant protein) was used as the positive control and water as the negative control (data not shown).
Statistics
Nonparametric tests were used. Data are presented as means ± SEM unless indicated otherwise. Differences between two groups were assessed using the Mann-Whitney U test. Data involving more than two groups were assessed by Kruskal-Wallis and Friedman’s ANOVA (with Dunn’s test for post hoc analysis), respectively. For Western immunoblotting experiments, the densities were measured using a scanning densitometer coupled to scanning software (ImageQuant; Molecular Dynamics via GE Healthcare). Spearman’s rank correlation was used for calculation of associations between variables, and P < 0.05 was considered significant.
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Results |
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Table 1
shows the anthropometric, biochemical, and hormonal data in PCOS and control women. Glucose, HOMA, 17ß-estradiol, testosterone, and androstenedione levels and free androgen index were significantly higher whereas SHBG was significantly lower in PCOS women. EIA analysis of serum RBP4 levels revealed that PCOS patients had significantly elevated levels when compared with controls (35.0 ± 2.4 vs. 25.0 ± 2.8 µg/ml; P < 0.05) (Table 1). Serum progesterone levels in all women confirmed follicular phase of the menstrual cycle.
mRNA expression of RBP4 and GLUT4 in normal and PCOS women
We detected RBP4 and GLUT4 mRNA in adipose tissue and in adipocytes, and subsequent sequencing of the PCR products confirmed the respective gene identities. Furthermore, real-time RT-PCR analysis corrected over ß-actin showed a significant increase of RBP4 in sc (*, P < 0.05) and om (**, P < 0.01) adipose tissues of PCOS women and a significant decrease of GLUT4 (*, P < 0.05) when compared with normal controls (Fig. 1, A and B). Similar findings were noted in isolated sc primary adipocytes from these women, in which PCOS women had significantly higher expression of RBP4 (#, P < 0.05) and significantly lower expression of GLUT4 (*, P < 0.05) when compared with normal controls (Fig. 1, C and D). Also, RBP4 mRNA expression was significantly increased in human sc adipocytes of all PCOS women and all normal controls (**, P < 0.01; ***, P < 0.001, respectively) when compared with corresponding sc adipose tissue (Fig. 1C). However, no significant difference in RBP4 or GLUT4 mRNA expression was observed when comparing corresponding om with sc adipose tissues in PCOS and normal subjects (Fig. 1, A and B, P > 0.05). To exclude endothelial cell contamination of the adipocytes, von Willebrand factor was examined, revealing its absence in adipocytes, using human umbilical vascular endothelial cells as the positive control. To exclude stromal cell contamination, gene expression of vimentin (supplemental Fig. 1, published as supplemental data on The Endocrine Society’s Journals Online web site), CD45, and CD14 were studied in isolated adipocytes. We found that there was negligible CD45 and CD14 gene expression when compared with adipose tissue (data not shown).
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The changes noted at mRNA level were also reflected at protein level in PCOS women, i.e. significantly greater RBP4 and significantly lesser GLUT4 levels in sc and om adipose tissues of PCOS women (Fig. 2, A and B; *, P < 0.05). There was no significant difference in ß-actin protein levels (Fig. 2, A and B, P > 0.05). Like mRNA, there was no significant difference (P > 0.05) in RBP4 or GLUT4 protein levels when comparing corresponding om with sc adipose tissues in PCOS and normal subjects (Fig. 2, A and B, P > 0.05). The detected protein for RBP4, GLUT4, and ß-actin had apparent molecular weights of 25, 45, and 45 kDa, respectively (Fig. 2, A and B, insets).
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RBP4 mRNA expression and protein levels were only significantly increased by 17ß-estradiol in human sc and om adipose tissue explants (Fig. 3, A and D; *, P < 0.05). RBP4 mRNA expression and protein levels was increased by testosterone as well as insulin and decreased by DHEA-S treatments, respectively, but these just failed to reach significance. There was no significant difference noted in RBP4 mRNA expression and net protein production with androstenedione treatment (Fig. 3, A and D, P > 0.05).
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GLUT4 mRNA expression and protein levels were significantly decreased by 17ß-estradiol and significantly increased by insulin (positive control) in human sc and om adipose tissue explants (Fig. 3, B and E; *, P < 0.05). Furthermore, GLUT4 mRNA expression was significantly increased by DHEA-S treatment in human sc adipose tissue explants (Fig. 3; *, P < 0.05). With this exception, like mRNA data, there were no significant differences noted in GLUT4 mRNA expression and protein levels with testosterone, androstenedione, and DHEA-S treatments, respectively (Fig. 3, B and E, P > 0.05).
Dose-dependent effects of testosterone, 17ß-estradiol, androstenedione, and DHEA-S on RBP4 secretion into the culture media from human om adipose tissue explants
RBP4 secretion into the culture media was only significantly increased dose dependently by 17ß-estradiol from human om adipose tissue explants (Fig. 4A; *, P < 0.05). However, there were no significant differences noted in RBP4 secretion with testosterone, androstenedione, and DHEA-S treatments, respectively (P > 0.05) (data not shown).
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When both groups were analyzed collectively, serum RBP4, sc and om adipose tissue RBP4 mRNA expression, as well as protein levels were positively associated with BMI, WHR, glucose, and 17ß-estradiol (P < 0.01), testosterone, androstenedione, DHEA-S (P < 0.05), and negatively associated with SHBG (P < 0.01), sc and om adipose tissue GLUT4 mRNA expression, as well as protein levels (P < 0.01). Similar findings were noted when the groups were analyzed individually (data not shown). Although we detected a significant positive correlation between serum RBP4 and glucose, we did not find any significant correlation between serum RBP4 and insulin or HOMA.
Given the observation that 17ß-estradiol increased RBP4 secretion into the culture media (Fig. 4A), when both groups were analyzed collectively, Spearman’s rank analyses demonstrated that serum RBP4 significantly positively correlated with serum 17ß-estradiol (Fig. 4B, r = 0.81, P < 0.01) but also sc adipose tissue mRNA expression (r = 0.88, P < 0.01), om adipose tissue mRNA expression (r = 0.67, P < 0.01), sc adipose tissue protein levels (r = 0.84, P < 0.01), and om adipose tissue protein levels (r = 0.78, P < 0.01). Similar findings were noted when the groups were analyzed individually (data not shown).
When both groups were analyzed collectively, Spearman’s rank analyses showed that GLUT4 significantly negatively correlated with serum 17ß-estradiol in sc adipose tissue mRNA expression (r = –0.77, P < 0.01), om adipose tissue mRNA expression (r = –0.69, P < 0.01), sc adipose tissue protein levels (r = –0.78, P < 0.01), and om adipose tissue net protein levels (r = –0.81, P < 0.01) (Fig. 4C–F). Similar findings were noted when the groups were analyzed individually (data not shown).
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Discussion |
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The up-regulation of RBP4 in women with PCOS, an IR and prodiabetic state, is of interest given that subjects with T2DM have higher serum/plasma RBP4 levels (5, 6) compared with controls, after accounting for BMI and WHR. In our study, it is unlikely that either BMI or WHR are responsible for higher RBP4 mRNA expression and protein levels in PCOS women, given that both groups were matched for these variables. Moreover, like others, we detected a significant positive correlation between serum RBP4 with BMI (14) and WHR (6, 14), although these were no different between PCOS and controls. Similar findings were noted with respect to RBP4 mRNA expression and protein levels in sc and om human adipose tissue depots.
Women with PCOS, particularly those who are overweight, have a higher incidence of IR (1). There are data in the literature in which some researchers have noted significant positive correlations between serum RBP4 and insulin (14) as well as plasma RBP4 and HOMA (6); however, like others (6, 14), although we detected a significant positive correlation between serum RBP4 and glucose, we did not find any significant correlation between serum RBP4 with either insulin or HOMA (6, 14). Indeed, this correlation may be spurious, without causative significance, resulting from the simple fact that our PCOS women had significantly higher fasting serum glucose levels. Similar findings were noted with respect to RBP4 mRNA expression and protein levels in both adipose tissue depots. Hence, it may be that the raised RBP4 levels observed in our PCOS women are not attributable to IR per se.
PCOS women, as in our study, have higher levels of gonadal and adrenal steroids (15). We found significant positive correlations between serum RBP4, RBP4 mRNA expression, and protein levels in both adipose tissue depots with gonadal and adrenal steroids. Furthermore, we provide novel evidence that 17ß-estradiol significantly increases RBP4 secretion (Fig. 4A) and up-regulates RBP4 mRNA expression and protein levels in human sc and om adipose tissue explants (Fig. 3, A and D). In relation to this, 17ß-estradiol has been shown to directly induce gene expression of another cellular retinoic acid-binding protein 2 in the rat uterus. This enhances retinoic acid activity and consequently affects expression of retinoid-responsive genes. The underlying mechanisms regulating cellular retinoic acid-binding protein 2 by 17ß-estradiol may be similar to that of RBP4 but remains to be further investigated (16, 17). Additionally, RBP4 mRNA expression and protein levels was increased by testosterone as well as insulin and decreased by DHEA-S treatments, respectively, but these just failed to reach significance. There was no significant difference noted in RBP4 mRNA expression and net protein production with androstenedione treatment (Fig. 3, A and D, P > 0.05).
In addition, we show that 17ß-estradiol, concurrently, significantly down-regulates GLUT4 mRNA expression and protein levels in human sc and om adipose tissue explants (Fig. 3, B and E). Moreover, correlation analyses revealed that, in sc and om adipose tissues, GLUT4 mRNA expression as well as protein levels were negatively associated with 17ß-estradiol (Fig. 4C–F).
Experiments in mice lacking adipose tissue GLUT4 suggest a reciprocal regulation of RBP4 by GLUT4 (5). However, we emphasize that our data does not necessarily imply that down-regulation of GLUT4 causes direct up-regulation of RBP4 by 17ß-estradiol. In fact, there is recent evidence to suggest the latter in humans as opposed to the tight reciprocal relationship between GLUT4 expression/glucose uptake in adipose tissue and RBP4 expression in rodents (7). It is possible that there may be other molecular mechanisms involved that have yet to be elucidated.
Rosenbaum et al. (18) showed that PCOS women have decreased sensitivity and responsiveness to insulin associated with diminished GLUT4 content in adipocytes. Additionally, there is ample evidence of impaired insulin signaling in the skeletal muscle contributing to the development of IR in PCOS women (19, 20, 21). Interestingly, studies in murine models demonstrated that RBP4 impairs insulin signaling in skeletal muscle (5). Hence, we tentatively hypothesize that the elevated RBP4 levels in serum and adipose tissue in overweight PCOS women as in our study may suggest a mechanism for the development of IR in the skeletal muscle of PCOS women.
A limitation of our study may relate to the number of subjects studied. However, obtaining BMI/WHR matched and menstrual cycle synchronized blood and tissue samples impeded subject recruitment. Also, it should be noted that estradiol levels can change significantly throughout the menstrual cycle. Therefore, it would be of interest to study RBP4 levels through the different stages of the menstrual cycle. This, unfortunately, could not be addressed in our present study. Notwithstanding, our observations are highly consistent and significant and raise interesting questions on the mechanisms regulating RBP4 expression.
In conclusion, we present novel data suggesting increased serum RBP4 levels as well as increased expression of RBP4 mRNA and protein levels in adipose tissue and adipocytes in overweight women with PCOS and their regulation by gonadal and sex steroids, in particular, 17ß-estradiol. The physiological and pathological significance of our findings remain to be elucidated but may indicate a mechanism for the development of IR in overweight women with PCOS. It would be of interest as to whether these observations also apply to lean PCOS women.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to declare.
First Published Online April 24, 2007
1 B.K.T. and J.C. contributed equally to this work. 
Abbreviations: DHEA-S, Dehydroepiandrosterone sulfate; EIA, enzyme immunoassay; GLUT4, glucose transporter 4; HOMA, homeostasis model assessment; IR, insulin resistance; om, omental; PCOS, polycystic ovary syndrome; PVDF, polyvinylidene difluoride; RBP4, retinol-binding protein 4; T2DM, type 2 diabetes mellitus.
Received January 16, 2007.
Accepted April 17, 2007.
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