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Mechanisms behind Lipolytic Catecholamine Resistance of Subcutaneous Fat Cells in the Polycystic Ovarian Syndrome

Departments of Medicine (G.F., M.R., H.W., P.A.) and Gynaecology (I.E.) at Huddinge University Hospital, Karolinska Institute, SE-141 86 Stockholm, Sweden

Address all correspondence and requests for reprints to: Peter Arner, M.D., Ph.D., Professor, Department of Medicine, M63, Huddinge University Hospital, Karolinska Institutet, SE-141 86 Stockholm, Sweden. E-mail: peter.arner{at}medhs.ki.se.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Lipolytic catecholamine resistance in sc fat cells is observed in polycystic ovarian syndrome (PCOS). The mechanisms behind this lipolysis defect were explored in vitro; sc fat cells were obtained from 10 young, nonobese PCOS women and from 14 matched, healthy control women. Fasting plasma glycerol levels were reduced by one third in PCOS (P < 0.05). Adipocytes of PCOS women were about 25% larger than in the controls (P < 0.05) and had 40% reduced noradrenaline-induced lipolysis (P < 0.05), which could be attributed to a 10-fold decreased ß₂-adrenoceptor sensitivity (P < 0.05) and low ability of cAMP to activate the protein kinase A (PKA)/hormone-sensitive lipase (HSL) complex (P < 0.05). In PCOS, the adipocyte protein content of ß₂-adrenoceptors, HSL, and the regulatory IIß-component of PKA were 70%, 55%, and 25% decreased, respectively (P < 0.001); but there was no change in the amount of the catalytic subunit of PKA or of ß₁-adrenoceptors. Thus, lipolytic catecholamine resistance of sc adipocytes in PCOS is probably attributable to a combination of decreased amounts of ß₂-adrenergic receptors, the regulatory IIß-component of PKA, and HSL. This may cause low in vivo lipolytic activity and enlarged sc fat cell size and promote later development of obesity in PCOS.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC OVARIAN SYNDROME (PCOS) is the most common endocrine disorder in women of reproductive age (1). It is well known that PCOS women are prone to become obese and develop a number of complications associated with obesity. The pathophysiological mechanisms responsible for the development of obesity in PCOS are less well known but may be multifactorial (2). Hyperandrogenism, which is a hallmark of PCOS and insulin resistance, could be of importance, as discussed (3, 4). Another possible factor might be an abnormal regulation of adipocyte lipolysis in PCOS. Subcutaneous fat cells from lean PCOS-subjects are resistant to the lipolytic effect of catecholamines (5), which are the major lipolysis-stimulating hormones in man (6). Decreased lipolytic activity could promote the development of obesity observed in PCOS through mechanisms discussed previously (6).

The molecular defects responsible for decreased ability of catecholamines to stimulate lipolysis in sc fat cells have been only partly elucidated in PCOS. It is essential to study these events in young and nonobese subjects. Obese non-PCOS subjects have, as lean PCOS women, lipolytic catecholamine resistance in their fat cells (7). Therefore, it is difficult to say, in obese PCOS subjects, what is attributable to obesity or to PCOS per se, as regards abnormalities in lipolysis regulation. It is important to study young subjects because age and hormonal changes during or after menopause may influence body weight regulation and lipid metabolism (8).

A decreased cell surface number of ß₂-adrenergic receptor (ß₂-AR) and yet-unidentified postreceptor defect(s) have been demonstrated in sc fat cells of young nonobese PCOS women (5). Catecholamine-induced lipolysis in human fat cells is subject to unique regulation (9). The hormones bind to lipolytic ß₁-AR, ß₂-AR, and ß₃-AR and also to antilipolytic ₂-AR. Usually, the ß-responses dominate, leading to increased cAMP formation, which, in turn, activates protein kinase A (PKA), followed by phosphorylation and activation of hormone-sensitive lipase (HSL) and, ultimately, accelerated hydrolysis of intracellular adipocyte triglycerides. Changes in the relative proportions between HSL and the different catalytic and regulatory components of PKA alter the lipolytic capacity of fat cells and, thereby, catecholamine-induced lipolysis, as discussed (10, 11).

In this study, we have investigated the mechanisms for impaired catecholamine-induced lipolysis in sc fat cells in PCOS, focusing on adrenoceptors and postreceptor activation at the PKA-HSL level. Adipocytes from young (<40 yr) nonobese control women and otherwise healthy nonobese PCOS women were investigated.

	Subjects and Methods

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Subjects and experimental protocol

Ten nonobese women with the diagnosis of PCOS, and a control group of 14 nonobese healthy women without clinical and biochemical signs of hyperandrogenicity, participated in the study. Only young (<40 yr) women were included. The women with PCOS were recruited from patients referred to the Department of Obstetrics and Gynaecology because of infertility. The diagnosis was based on clinical findings (infertility, hirsutism) and an elevated ratio (>0.063) of serum total testosterone to SHBG and a LH/FSH ratio above 1 on a minimum of 2 occasions during a period of 6 months before examination. Polycystic ovaries were confirmed by gynecological examination and intravaginal ultrasound technique. Body mass index (BMI) ranged from 18–26 kg/m² and age from 19–39 yr. Patients and controls took no medication. The study was approved by the ethics committee at the Karolinska Institute. The protocol was explained in detail to each participant, and her consent was obtained. The women were examined at 0800 h, after an overnight fast. The investigations were performed in the early follicular phase (i.e. the week after menstruation). Waist to hip ratio and BMI were determined. Body fat content was measured by bioelectrical impedance using a TBF-305 body fat analyzer (Tanita/Stellar Innovations, Inc., Tokyo, Japan). This method shows a strong correlation to measurements with dual energy x-ray absorptiometry, according to the manufacturer (http://www.tanita.com). After 30 min of rest in the supine position, a venous blood sample was obtained for analysis of serum or plasma concentrations of insulin, testosterone, SHBG, glucose, cholesterol, and triglycerides, as described previously (5). In addition, plasma glycerol was determined by a bioluminescence method (12). The ratio between testosterone and SHBG was used as an index of biologically active testosterone (13). The so-called insulin sensitivity index or homeostasis (HOMA) model was used to calculate in vivo insulin sensitivity according to the formula: fasting plasma glucose (mM) x fasting plasma insulin (mU/liter) x 22.5^-1 (14). The HOMA index shows a good correlation (r = 0.88) to the so-called golden standard for insulin sensitivity index, the euglycemic hyperinsulinemic clamp (14), and has recently been proven valid for assessing in vivo insulin sensitivity in PCOS (15). An sc fat biopsy was obtained, during local anesthesia, from the abdominal region (16). One piece of tissue (about 300 mg) was immediately removed, quickly washed in saline, frozen in liquid nitrogen, and kept at -70 C for subsequent protein determination. The remaining part was used for a lipolysis experiment. In 2 control and 3 PCOS women, the amount of adipose tissue was too small for lipolysis experiments.

Isolation of fat cells and determination of lipolysis and fat cell size and number

The experiments were conducted exactly as described (5). In brief, isolated fat cells were prepared by collagenase treatment, and mean fat cell volume and number of fat cells incubated were determined. Dilute suspensions of isolated fat cells were incubated in duplicate in buffer containing albumin (20 g/liter), glucose (1 g/liter), and ascorbic acid (0.1 g/liter) in the absence or presence of increasing concentrations (10^-12–10^-4 M) of noradrenaline (endogenous agonist stimulating ß- and ₂-ARs), dobutamine (selective ß₁-AR agonist), terbutaline (selective ß₂-AR agonist), CGP 12177 (selective ß₃-AR agonist), clonidine (selective ₂-AR agonist), forskolin (adenylyl cyclase stimulator), and dibutyryl cAMP (phosphodiesterase-resistant cAMP analog). In the clonidine experiments, adenosine deaminase (1 U/ml) was added to remove traces of adenosine, which might interfere with the antilipolytic effect of clonidine. After 2 h, an aliquot was removed for determination of glycerol (lipolysis index) by a bioluminescence assay (12). The concentration of agonist producing the EC₅₀ was determined in the experiments with the AR selective agonists. The negative logarithm of the EC₅₀ value (pD₂) was defined as the AR sensitivity. Glycerol release at maximum effective concentration (responsiveness) was determined for noradrenaline, forskolin, and dibutyryl cAMP.

Protein isolation and Western blot analysis

The studies were conducted exactly as described before (17). In brief, approximately 300 mg frozen tissue was crushed and lysed in protein lysis buffer supplemented with protease inhibitors and homogenized. The homogenate was centrifuged, and the infranatant was removed and saved at -70 C. The protein content in each sample was determined. One hundred micrograms of total protein was then loaded on 12% polyacrylamide gels and separated by standard SDS-PAGE. Samples from PCOS and control subjects were run on the same polyvinylidine fluoride membranes. Blots were blocked for 1 h at room temperature in Tris-buffered saline with 0.1% Tween 20 and 5% nonfat dried milk. This was followed by an overnight incubation at +4 C in the presence of antibodies directed toward either ß₁-AR, ß₂-AR, HSL, the catalytic region of PKA (PKAcat), or the regulatory regions of PKA: I and IIß (PKA-reg I and PKA-reg IIß). The PKA-antibodies were from Transduction Laboratories, Inc. (Lexington, KY). The ß₁-AR and ß₂-AR antibodies were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). To confirm antibody specificity, positive controls were included in all experiments as provided by all manufacturers. HSL antibodies were generated as described below. Secondary antibodies, conjugated to horseradish peroxidase, were from Sigma (St. Louis, MO; -mouse, rabbit, and -chicken). Antigen-antibody complexes were detected by chemiluminescence, using a kit of reagents from Pierce Chemical Co. (Supersignal, Rockford, IL), and blots were exposed to high-performance chemiluminescence film (Amersham, Little Chalfont, UK). Films were scanned, and the OD of each specific band was analyzed using the program NIH Image (NIH, Bethesda, MD) and expressed as OD/mm^-2 x 100 µg^-1 total protein. One gel could handle 14 samples. In the first gel, 5 PCOS and 9 controls were used. The other gel contained all remaining samples plus one of the controls from gel 1. The latter sample was used to normalize OD reading between blots.

HSL antibodies

The HSL antibody was generated exactly as described (18). In brief, human HSL exists in two forms because of alternative splicing of exon 6. These are commonly referred to as HSL-long and HSL-short. In the present study, we used an antibody that recognizes both forms, which was generated in chicken. Immunized chicken antiserum was affinity-purified against recombinant rat HSL. The affinity-purified antibody was shown to be specific for both forms of HSL.

Drugs and chemicals

BSA (Fraction V, A4503) Clostridium histolyticum collagenase type 1, glycerol kinase from Escherichia coli (C-0130), forskolin, and clonidine were from Calbiochem (Calbiochem, LA Jolla, CA). Noradrenaline and dibutyryl cAMP were obtained from Sigma. Adenosine deaminase was of calf intestine origin and was supplied by Roche Diagnostics Scandinavia AB (Bromma, Sweden). Dobutamine hydrochloride was purchased from Eli Lilly \|[amp ]\| Co. (Indianapolis, IN), and terbutaline sulfate was obtained from Astra USA, Inc. (Lund, Sweden). CGP (±)12177 [(-)-4-(3-t-butylamino-2-hydroxy-propoxy)-benzimidazole-2-one] was from Ciba-Geigy (Basel, Switzerland). ATP monitoring reagent, containing firefly luciferase, came from Biothema (Stockholm, Sweden). All other chemicals were of the highest grade of purity that was commercially available.

Statistics

Values are mean ± SEM or (when indicated) ± SD. Student’s two-tailed unpaired t test was used for comparison of data between groups. All statistics were analyzed by means of a standard software statistical package. A P value of 0.05 or less was considered to be statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Clinical characteristics

Clinical data are given in Table 1. The nonobese women with PCOS showed equal age, BMI, body fat content, waist to hip ratio and fasting circulating levels of insulin, glucose, and lipids, compared with the nonobese healthy women. In addition, their in vivo insulin sensitivity was normal, as judged by mean values for HOMA index. However, the fat cell volume was 25% larger in PCOS than the control state (P < 0.05). Total serum levels of testosterone were increased and SHBG levels decreased in PCOS. Likewise, the testosterone/SHBG ratio was markedly increased in PCOS. In this group, values for this ratio ranged from 0.064–0.1210; and in the control women, from 0.004–0.060.

Lipolysis experiments

Lipolysis data are shown in Table 2. There was no difference in the basal rate of lipolysis between PCOS and control subjects. However, the lipolytic responses of noradrenaline, forskolin, and dibutyryl cAMP were about 40% reduced in adipocytes from women with PCOS, compared with that in healthy women (P = 0.02–0.03). The ß₂-AR subtype-selective agonist terbutaline did also elicit an impaired lipolytic response in the PCOS women, compared with the normal women. The reduction was displayed by a one-log-unit-lower pD₂ (P = 0.02), which indicates a 10-fold less ß₂-AR sensitivity. In contrast, pD₂ for the ß₁-AR-selective agonist dobutamine, the ß₃-AR-selective agonist CGP-12177, and the ₂-AR-selective agonist clonidine showed no difference between the groups. Adenosine-deaminease-induced lipolysis was calculated (glycerol release from cells incubated with adenosine deaminease minus glycerol release in the basal state). Values (µmol glycerol/2 h·10⁷cells) were 2.1 ± 0.03 and 2.3 ± 0.04 in controls and PCOS women, respectively, and, thus, almost identical.

The first Western blot containing most of the subjects (five PCOS, nine controls) is depicted in Fig. 1. The combined results of antibody experiments with the two Western blots are summarized in Table 3. For adrenoceptor proteins, a 70% reduction in the ß₂-AR levels was observed in PCOS fat cells (P = 0.0001), but there was no difference between groups in the ß₁-AR levels (the latter results are not shown in Fig. 1). For HSL, only one band, representing the HSL-long form, was detected, and the adipocyte amount was reduced by 55% in PCOS (P < 0.01). For the PKA complex, the adipocyte content of PKA-regIIß was reduced by about 25% in PCOS-subjects (P < 0.001), whereas the amount of the catalytic component did not differ between groups. However, we did not observe detectable levels of PKA-RegI.

View larger version (38K): [in this window] [in a new window]   Figure 1. Results of Western blot experiment. One of the two blots is depicted. One hundred micrograms of adipocyte protein extract were separated by SDS-PAGE and transferred to blots, where specific proteins were detected with primary antibodies directed against the indicated proteins. Blots were quantified, and results are summarized in Table 3.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The catecholamine resistance could be divided into two plausible mechanisms. First, there was a selective decrease in ß₂-AR sensitivity in the PCOS women, whereas ß₁-, ß₃-, and ₂-AR sensitivities were unchanged. The second finding was an impaired maximum lipolytic response in the PCOS women. The latter reduction was of a similar magnitude when lipolysis was stimulated by the natural ligand noradrenaline, at the adenylate cyclase level with forskolin or at the PKA level with dibutyryl cAMP. This indicates a defect located at the most distal steps of the lipolytic cascade, i.e. PKA and/or HSL. These findings with lipolysis are almost identical to those observed previously in another cohort of young and nonobese women with PCOS (5), which further suggests that the lipolytic abnormality could be a hallmark of PCOS.

The mechanisms underlying the decreased catecholamine-induced lipolysis in sc fat cells in PCOS are, at least partly, revealed from the Western blot experiments. The average ß₂-AR content was significantly (70%) reduced, but there was no significant change in ß₁-AR content. This is in agreement with earlier radioligand binding studies showing 50% decreased adipocyte cell surface number of ß₂-AR but no change in ß₁-AR number in PCOS (5). The 20% difference between the two studies in ß₂-AR might be explained by the fact that in the previous study, only cell surface receptors were quantified (5). The novel mechanistic findings concern the previously unknown postreceptor defect (5). The adipocyte protein content of the long form of HSL was decreased by 55%, and that of the regulatory IIß-subunit of PKA was reduced by 25% in PCOS. However, there was no alteration in the amount of PKAcat. The meaning of reduced PKA-regIIß in human fat cells is unclear for the moment. However, mice lacking RIIß have a markedly reduced catecholamine-induced lipolysis in their fat cells (18). Furthermore, previous human data show that a low amount of HSL-long in human sc fat cells is associated with reduced ability of cAMP to activate lipolysis (19). Therefore, it is quite possible that a combination of decreased protein amounts of ß₂-AR, PKA-RIIß, and HSL-long makes sc fat cells resistant to the lipolytic action of catecholamines in PCOS. It is not likely that there is a generalized alteration in lipolytic signaling proteins in fat cells from PCOS. If so, there should have been a change in PKAcat and ß₁-AR, which instead were similarly expressed in fat tissue from the two groups.

It is of interest to compare data with the PKA-HSL complex in the present study on sc fat cells with those published on visceral (omental) fat cells (17). In both studies, the same type of women were investigated, and Western blot experiments were identical. No PKA-regI was found in sc cells, but this protein was clearly present in the omental cells. No HSL-short was present in the sc region; but, at least, control women had significant amounts of this protein in their omental fat cells. It is therefore likely that regulation of lipolysis, at its most distal levels, differs substantially between the two fat depots.

Another relevant comparison of present and previous (5, 17) data concerns the regional differences in lipolysis between PCOS and control women. Catecholamine-induced lipolysis is reduced in the sc fat but increased in the visceral fat in PCOS. This might, at least in part, explain the adverse metabolic profile and obesity often seen in PCOS. The lipolytic resistance in sc fat cells could promote obesity, whereas the enhanced visceral fat lipolytic activity and resulting excess delivery of fatty acids to the liver could lead to hyperinsulinemia, glucose intolerance, and dyslipidemia (6, 20, 21). Interestingly, there are also regional variations in the antilipolytic effect of insulin in PCOS. A normal response is observed in visceral fat cells (17) and decreased response in sc adipocytes (22, 23).

In summary, this study suggests that lipolytic catecholamine resistance in sc fat cells of PCOS women is attributable to decreased protein levels of ß₂-AR, PKA-RegIIß, and HSL. This may decrease in vivo lipolytic activity and increase lipid content of fat cells and, in turn, promote the later development of obesity in PCOS.

	Acknowledgments

 
The excellent technical assistance of Britt-Marie Leijonhufvud, Katarina Hertel, Eva Sjölin, and Kerstin Wåhlén is greatly appreciated. We thank Cecilia Holm, Lund University, for the HSL antibody.

	Footnotes

 
This work was supported by grants from Åke Wiberg Foundation, Tore Nilsson Foundation, Swedish Medical Society and Foundation for Scientific Work in Diabetes, Swedish Research Council, Swedish Heart and Lung Association, Swedish Diabetes Association, and Novo Nordic Fund.

G.F. and M.R. contributed equally to the study.

Abbreviations: AR, Adrenergic receptor; BMI, body mass index; HOMA, insulin sensitivity index; HSL, hormone-sensitive lipase; PCOS, polycystic ovarian syndrome; PKA, protein kinase A; PKAcat, the catalytic region of PKA.

Received October 8, 2002.

Accepted January 23, 2003.

	References

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