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Reproductive Endocrinology |
Departments of Medicine and Gynecology and Obstetrics, and the Research Center, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden
Address all correspondence and requests for reprints to: Hans Wahrenberg, M.D., Division of Endocrinology and Metabolism, Department of Medicine M63, Huddinge Hospital, Karolinska Institute, S-141 86 Huddinge, Sweden.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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2-sensitivity) or
ß1-adrenoceptor density; second, the maximum lipolytic
response was also 35% lower (P < 0.02) in the
PCOS women compared to that in the healthy women. This was seen with
all ß-adrenergic agonists and the postreceptor-acting agents
forskolin (activating adenylyl cyclase) and dibutyryl cAMP (activating
protein kinase). Neither ß2-adrenoceptor sensitivity or
density nor the reduced lipolytic responsiveness was restored by 3
months of oral contraceptives treatment. The results indicate the
existence of a marked impairment of catecholamine-induced lipolysis in
nonobese PCOS women displaying early features of the insulin resistance
syndrome due to multiple lipolysis defects as a lower
ß2-adrenoceptor density and reduced function of the
protein kinase, hormone-sensitive lipase complex. These lipolysis
defects are identical to those observed in the insulin resistance
(metabolic) syndrome and could be a primary pathogenic mechanism for
the development of these disorders. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Because of the strong link between regional fat distribution and the
insulin resistance syndrome, it is possible that factors directly
related to adipocyte triglyceride metabolism are of importance for the
development of insulin resistance-related disorders. The uptake of
triglycerides to adipose tissue is regulated by adipose tissue
lipoprotein lipase, and the breakdown of triglycerides in adipocytes is
regulated by catecholamines and insulin, which stimulate and inhibit,
respectively, hormone-sensitive lipase (13). In human adipose tissue,
catecholamines stimulate lipolysis through ß1- and
ß2-adrenoceptors (-ARs) and inhibit lipolysis through
2-ARs. Recently, a third ß-AR, namely
ß3-AR, has been found to be functional in man, especially
in the omental fat depot (14, 15). Noradrenaline resistance due to a
reduced ß2-AR density has been found in a group of upper
body obese women as well as in men with all features of the insulin
resistance syndrome (16, 17). In the latter group there was also an
additional defect in the hormone-sensitive lipase complex. Thus,
androgens could be a putative regulatory factor of the lipolytic
system, thereby governing the accumulation of fat in specific areas,
leading to upper body obesity. The aim of the present study was to
obtain insight into the regulatory effect of androgens on the lipolytic
process by studying adrenergic regulation in abdominal sc adipocytes of
nonobese women with PCOS before and after hormonal therapy compared to
that in an age- and weight-matched group of healthy women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ten nonobese women with the diagnosis of PCOS and a control
group of 11 nonobese healthy women without clinical and biochemical
signs of hyperandrogenicity volunteered to participate in the study.
The women with PCOS were recruited from patients referred to the
infertility unit at the Department of Obstetrics and Gynecology. The
diagnosis was based on clinical findings of infertility, hirsutism,
oligomenorrhea, a ratio of serum total testosterone to sex
hormone-binding globulin (SHBG) greater than 0.063, and a LH/FSH ratio
above 1 on a minimum of two occasions during a period of 6 months
before examination. Polycystic ovaries were confirmed by gynecological
examination and intravaginal ultrasound technique. Obesity was defined
as a body mass index (BMI) above 27 kg/m2. Patients and
controls took no medication. The clinical characteristics of the PCOS
women and the control group are given in Table 1
. The
study was approved by the ethics committee at Karolinska Institute. The
protocol was explained in detail to each participant, and their
consents were obtained. The women were examined at 0800 h after an
overnight fast. Initially, ultrasound examination was performed to
exclude pregnancy and to confirm that the women were in the follicular
phase of the menstrual cycle. Waist/hip ratio, BMI, and blood pressure
were determined. After 30 min of rest in the supine position, a serum
sample was obtained for analysis of hormones, SHBG, glucose, and
lipids. Serum concentrations of cortisol, testosterone, glucose,
cholesterol, and triglycerides were determined at the hospital’s
clinical chemistry laboratory by established routine methods. The ratio
between testosterone and SHBG was used as an index of biologically
active testosterone (18). Serum androstenedione and
dehydroepiandrosterone and its sulfate were determined at the hormone
laboratory, Department of Obstetrics and Gynecology, using
radioimmunological methods (19, 20). Serum insulin was measured by RIA
using a commercial kit obtained from Pharmacia-Upjohn Diagnostics
(Stockholm, Sweden). A sc fat biopsy of adipose tissue (
3 g) was
obtained during local anesthesia from the abdominal region randomly
from the left or right side at the middle to the umbilicus (21). Eight
of the 10 women with PCOS volunteered to be reexamined according to the
protocol described above after a 3-month period of treatment with a low
dose combined contraceptive pill (Orthonett novum, Cilag AG,
Schaffhausen, Switzerland) containing 0,5 mg norethisterone and 35 µg
ethinyl estradiol. The second examination was performed in the same
manner as the first one, except the biopsy was taken from the
contralateral side.
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Isolated fat cells were prepared according to the collagenase method described by Rodbell (22). Direct microscopic determination of the diameter of 100 fat cells was performed as described previously (23). The coefficient of variation was about 3%. Mean fat cell volume, surface area, and weight were determined as previously described (24). The number of fat cells incubated was calculated as follows. The lipid content of the aliquot was determined gravimetrically after solvent extraction. The lipid content of the incubated fat cells was then divided by the mean fat cells weight, assuming that the lipids constitute more than 95% of the fat cell weight.
Lipolysis experiments
Isolated fat cells were incubated as described in detail
previously (25). In brief, about 5,000-10,000 cells/mL were incubated
in duplicate at 37 C in Krebs-Ringer phosphate (pH 7.4) containing
albumin (20 g/L), glucose (1 g/L), and ascorbic acid (0.1 g/L) in the
absence or presence of increasing concentrations
(10-16-10-4 mol/L) of noradrenaline
(endogenous agonist stimulating ß- and 2-ARs),
terbutaline (selective ß2-AR agonist), dobutamine
(selective ß1-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 mU/mL) was added to the
incubation medium to remove traces of adenosine, which may interfere
with the antilipolytic effect of clonidine (25). After 2 h, an
aliquot was removed for determination of glycerol. The concentration of
agonist producing the half-maximum effect (EC50) was
determined using logistic conversion of each dose-response curve as
described previously (26). The negative logarithm of the
EC50 value (pD2) was defined as the AR
sensitivity.
ß-AR binding studies
Receptor binding studies have been described in detail previously (25). Isolated fat cells (20,000 cells/mL) were incubated at 37 C in 0.5 mL Krebs-Ringer phosphate buffer (pH 7.4) containing albumin (5 g/L), glucose (1 g/L), and ascorbic acid (0.1 g/L). Saturation experiments were performed to determine the total amount of ß-ARs. The cells were incubated in duplicate for 60 min with six different concentrations of [125I]cyanopindolol ([125I]CYP). Nonspecific binding determined in the presence of 0.1 µmol/L propranolol was about 30% at low and about 45% at high radioligand concentrations. Competition experiments were performed in duplicate to determine the fraction of ß2-ARs of the total ß-receptor population; 100 pmol/L [125I]CYP competed with 12 increasing concentrations of the ß2-specific antagonist ICI 118,551 (10-11-10-4 mol/L). Nonspecific binding at 10-4 mol/L ICI 118,551 was about 30% and did not differ from nonspecific binding determined by 0.1 µmol/L propranolol. The binding experiments were evaluated by computerized curve fitting (Ligand, Biosoft, Ferguson, MO) (27). The software calculates estimates of the maximum total binding capacity obtained from the saturation binding experiments as well as the affinity constants (Kd) and the proportion of ß1- and ß2-ARs accessed from the displacing experiments by ICI 118,551. At the concentrations of [125I]CYP used in these experiments, there was no significant binding to ß3-ARs. Instead, the radioligand bound with homogeneity to ß1- and ß2-ARs, yielding linear Scatchard curves with slopes near 1.
Drug and chemicals
BSA (fraction V 63F 0748), Clostridium histolyticum collagenase type 1, glycerol kinase from Escherichia coli (G4 509), forskolin, dibutyryl cAMP, and d,l-propranolol were obtained from Sigma Chemical Co. (St. Louis, MO), (-)isoprenaline hydrochloride was obtained from Hässle (Mölndal, Sweden). Terbutaline sulfate was purchased from Draco (Lund, Sweden), dobutamine hydrochloride was obtained from Eli Lilly Co. (Indianapolis, IN), and ICI 118,551 was purchased from Cambridge Research Biochemist (Sessyr, UK). ATP monitoring regent containing fire fly luciferase was obtained from LKB Wallac (Turku, Finland). [125I]CYP was obtained from New England Nuclear (Boston, MA). All other chemicals were of the highest grade of purity commercially available.
Statistics
Student’s two-tailed t test was used for comparison
of data between (unpaired) and within groups (paired). The
SD was used as a measure of dispersion of clinical
characteristics data (Table 1
), and the SEM was used in
experimental data. All statistics were analyzed by means of a standard
software statistical package. Values for nonnormally distributed
parameters such as Kd and EC50 were transformed
into the logarithmic form before statistical analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The women with PCOS showed several features of the insulin
resistance syndrome, such as higher waist/hip ratio, fasting insulin
level, fasting blood glucose level, and triglyceride level, despite
equal BMI and age, compared with the nonobese healthy women (Table 1).
Lipolysis experiments
There was no difference in the basal rate of lipolysis between
nonobese women with PCOS and healthy control subjects (7.4 ± 1.4
and 6.2 ± 1.2 µmol glycerol/107 cells·2 h,
respectively). However, the lipolytic response of the endogenous
catecholamine noradrenaline was markedly reduced in adipocytes from
women with PCOS compared to that in healthy women. The maximum
lipolytic response was 40% lower (P < 0.05) and the
lipolytic sensitivity (pD2) was 7-fold lower in the PCOS
women than those in the healthy women (P < 0.001; Fig. 1A and Tables 2 and 3).
The ß2-AR subtype-selective agonist terbutaline also
elicited an impaired lipolytic response in the PCOS women compared to
that in the normal women, with a calculated 7-fold lower
pD2 (P < 0.005) and a 35% lower
responsiveness than controls (P < 0.03; Fig. 1C and
Table 2). In contrast, the ß1-subtype-selective agonist
dobutamine did not show any shift of the dose-response curves,
indicating similar sensitivity for the agonist in both groups, but the
amplitude was reduced in the PCOS women. The pD2 values
were about 7.6 - log mol/L in both groups, and responsiveness was 35%
reduced in PCOS (P < 0.02; Fig. 1D and Tables 2 and 3). In both groups, the basal lipolysis rate was similarly inhibited by
about 50% in a dose-dependent manner by the 2-agonist
clonidine, with no observed differences in clonidine sensitivity or
responsiveness (Fig 1B and Tables 2 and 3).
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and Table 2). Thus, the responsiveness to forskolin
was 30% lower (P < 0.05), and that to dibutyryl cAMP
was about 35% lower (P < 0.02) in the PCOS patients
compared to the healthy women. There was a slight, but not significant,
difference in adipocyte size between both groups (553 ± 43 pL in
the PCOS group vs. 490 ± 38 pL in the healthy
subjects). The data were expressed using cell number as the
denominator. If the data were expressed per g lipid, the differences in
lipolytic response between the two groups become even more marked.
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The total ß-AR density was slightly lower in the PCOS group than
in the healthy group, although the difference was not statistically
different as determined from Scatchard analysis of individual
saturation experiments with [125I]CYP (Fig. 3). Displacement of [125I]CYP by the
selective ß2-antagonist ICI 118,551 showed shallowed and
biphasic curves that fit significantly better to a two-site than to a
one-site model. From these curves a fraction of ß1- and
ß2-ARs could be calculated as well as the affinity
constants for each receptor subtype. Combining the results from the
saturation and displacement experiments for each individual allowed
calculation of an estimate of the total number of each receptor
subtype. The PCOS women showed a 50% lower ß2-AR density
[1.6 attomoles (amol)/mm2 in the PCOS women and 2.9
amol/mm2 in the healthy women, respectively;
P < 0.02; Fig. 3]. There was no significant
difference in the density of the ß1-AR subtype (1.6 and
1.4 amol/mm2 in PCOS and healthy women, respectively; Fig. 3). There was no significant difference between the both groups with
regard to receptor affinity (Kd) for the displacing drug
ICI 118,551 or the radioligand, respectively (data not shown).
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Treatment of the PCOS women with OC for 3 months significantly
increased the SHBG level, resulting in a normalization of the free
testosterone level, as judged by the testosterone/SHBG ratio (Table 1).
There were no significant changes in fasting insulin, blood glucose, or
triglyceride levels after OC therapy, indicating that insulin
resistance and lipid abnormality were still present.
The concentration-response curves for the lipolytic agents were almost
superimposable when the PCOS patients were compared before and after
hormone treatment (Tables 2 and 3). Fat cell size and basal lipolysis
rates did not change during OC treatment. Moreover, there were no
influence on ß1- and ß2-AR densities (Fig. 3) or binding affinities (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The chief finding in adipose tissue was a marked lipolytic
catecholamine resistance among the PCOS women compared to the healthy
control women. The catecholamine resistance could be divided into two
components: 1) a 7-fold decreased lipolytic sensitivity, and 2) an
approximately 35% reduction in the maximum lipolytic response to
challenge with the endogenous catecholamine noradrenaline. Moreover,
the decreased lipolytic sensitivity to noradrenaline could be
attributed to a selective decrease in ß2-AR sensitivity
in the PCOS women, whereas ß1- and 2-AR
sensitivities were unchanged. The reduced ß2-AR
sensitivity, in turn, was related to a corresponding selective loss of
about 50% of the ß2-AR-binding sites in the adipose
tissue from the PCOS women compared to those in the healthy controls.
This indicates that a low ß2-AR density may be of major
importance for the development of catecholamine resistance. A reduced
ß2-AR density has been found in upper body obese women
with slight signs of the metabolic syndrome and in men with several
marked features of the metabolic syndrome (16, 17). Taken together,
this indicates that a reduced ß2-AR function could be a
common key factor in these different insulin-resistant states. The
change in ß2-AR density is well within the magnitude
required to explain the 7-fold decrease in ß2-adrenergic
sensitivity, as the ß-AR family acts as spare receptors (28).
Recently, the ß3-AR has been recognized as being
functional in man, especially in omental fat (14, 15). However, in
abdominal sc adipose tissue it plays only a minor role as a lipolysis
regulator (29), and it does not interfere with the ß1-
and ß2-subtype-selective agonists used in this study.
Furthermore, the ß3-AR has 100- to 1000-fold less
affinity for the radioligand [125I]CYP and would not be
detected at the radioligand concentration used in our study. This is
further emphasized by linear Scatchard plots and Hill coefficients
close to 1 in our radioligand experiments.
The second finding of catecholamine action was an impaired maximum lipolytic response in the PCOS women. The impairment was of similar magnitude when lipolysis was stimulated by the various ß-AR agonists, at the adenylate cyclase level with forskolin, or at the protein kinase A level with dibutyryl cAMP. This indicates an additional defect in the adipocytes from the PCOS women that is located at the most distal steps of the lipolytic cascade, i.e. the protein kinase A complex, or at the hormone-sensitive lipase enzyme. The observed postreceptor changes in the lipolytic system in the abdominal sc adipocytes from PCOS women mimic the findings in abdominal sc fat cells of older men with the fully developed metabolic syndrome (17). In contrast, Rebuffé-Scrive and co-workers did not find any difference in noradrenaline-stimulated adipocyte lipolysis between healthy women and nonobese and obese PCOS women (30). However, the latter study was performed in a small number of patients with only maximum concentrations of noradrenaline, and it focused on regional differences in metabolism between femoral and abdominal sites. However, the presence of a similar postreceptor defect and a low ß2-AR density in PCOS and the metabolic syndrome further strengthens the idea that an abnormal adipocyte function might be a key link between these two different insulin-resistant states. Indirect evidence for a pathogenic role of the ß2-AR in the development of insulin resistance is the fact that unselective ß-blockers produce a more marked insulin resistance than ß1-selective blockers (31, 32), and a combined ß1-blocker with ß2-agonistic properties does not induce insulin resistance (33). Furthermore, treatment of obese and insulin-resistant laboratory animals with selective ß2-agonists normalizes insulin action and body weight (reviewed in Refs. 34 and 35).
A role for androgens in the development of metabolic disorders in PCOS as well as in the insulin resistance syndrome in men has been suggested (9, 36, 37). However, the role of androgens, particularly testosterone, in the pathogenesis of these disorders is obscure, as testosterone has opposite actions in men and women. In men, a low serum testosterone level is associated with the metabolic aberrations of the insulin resistance syndrome. Moreover, in male rats, testosterone seems to up-regulate ß-AR density as well as postreceptor events close to the protein kinase A-hormone-sensitive lipase level (38, 39, 40). In women, androgen excess is frequent, but not always associated with the insulin resistance syndrome. However, in the eight PCOS women in our study who were treated with contraceptive pills for 3 months, which normalized their androgen levels, no effect was observed on the in vivo metabolic abnormalities or on the lipolytic defects in vitro. Moreover, GnRH agonists and estrogen have not been successful in reverting insulin resistance or the metabolic disturbances in PCOS women (30, 41, 42). In fact, there is far more evidence for insulin resistance and hyperinsulinemia as the primary cause of ovarian hyperandrogenism in PCOS than the reverse (43). Reducing insulin resistance with metformin ameliorates hyperandrogenicity in obese PCOS women (44). It is tempting to speculate that catecholamine resistance in sc adipose tissue is a primary defect, causing a compensatory increase in sympathetic activity, inducing insulin resistance and hyperinsulinemia, and causing secondary hyperandrogenicity and metabolic disturbances in susceptible women.
Recently, it has been shown that subjects with abdominal obesity have increased lipolysis in omental fat cells due to an increased ß3-AR sensitivity that favors increased lipolysis from the omental depot and thereby an increased flux of free fatty acids to the liver, mediating the metabolic disturbances of an increased sympathetic drive (15). Whether PCOS is associated with increased lipolysis in omental fat as well is not known at present. For ethical reasons, this fat depot cannot be investigated in a clinical setting with healthy subjects.
In conclusion, the present study demonstrates for the first time a defect in lipolysis regulation of the abdominal adipocytes from nonobese women with PCOS due to a lower ß2-AR density and a reduced function of the protein kinase A-hormone-sensitive lipase complex compared to those in healthy nonobese women. This defect is similar to that observed in the insulin resistance syndrome, indicating that a defect in adipocyte function could be a link between these two insulin-resistant conditions. Furthermore, the defect in lipolysis regulation is not directly linked to hyperandrogenicity per se.
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Acknowledgments |
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Footnotes |
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Received May 29, 1996.
Revised November 22, 1996.
Accepted December 30, 1996.
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References |
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