| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Studies |
Department of Medicine and Research Center, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
Address all correspondence and requests for reprints to: Peter Arner, M.D., Department of Medicine, Huddinge Hospital, S-141 86 Huddinge, Sweden.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
2-adrenoceptor agonist), but 15
times enhanced sensitivity to terbutaline (selective
ß2-adrenoceptor agonist; P < 0.01).
Moreover, thyrotoxicosis was accompanied by a 3-fold increase in
ß2-adrenoceptor number (P < 0.005),
but unchanged ß1-adrenoceptor levels. Further, the
lipolytic effects of dibutyryl cAMP (activating protein kinase A and
thereby hormone-sensitive lipase) and forskolin (activating adenylate
cyclase) were about 60% enhanced (P < 0.005). No
change in the maximum activity of the hormone-sensitive lipase could be
demonstrated in the hyperthyroid state compared to that in the
euthyroid state. The observed abnormalities in lipolysis and
ß2-adrenoceptor number were normalized after antithyroid
treatment. It is concluded that in human hyperthyroidism, the
interactions between thyroid hormone and catecholamines in adipocytes
involve abnormalities at both receptor and postreceptor levels. The
former mechanism seems to be a selective increase in the expression of
the ß2-adrenoceptors. The latter mechanism involves
increased ability of cAMP to activate hormone-sensitive lipase, but not
a change in maximum enzyme capacity. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In hyperthyroidism, excess thyroid hormones have marked metabolic
effects, such as enhancement of oxygen consumption and thermogenesis as
well as increased lipid mobilization; all factors that promote weight
loss. The enhanced lipolytic response to catecholamines found in fat
cells of hyperthyroid subjects has been attributed to an increased
total number of ß-adrenergic (i.e. ß1 plus
ß2) receptors (2) as well as decreased phosphodiesterase
activity (3). Both changes are accompanied by increased levels of cAMP
after catecholamine stimulation. Three ß-adrenoceptor subtypes are
expressed in human fat cells: the ß1- and
ß2-receptors, which are dominant in sc fat cells, and the
ß3-receptor, mainly found (together with
ß1- and ß2-receptors) in visceral fat cells
(4). In addition, catecholamine-induced lipolysis can be modified by
antilipolytic 2-adrenoceptors (5).
Earlier detailed studies in laboratory animals have shown that treatment with thyroid hormones results in unaltered (6, 7) as well as increased (8) numbers of ß-adrenoceptors. The ß1-adrenoceptor, but not the ß2-adrenoceptor, subtype is sensitive to up-regulation in adipose tissue (7, 9) as well as in ventricular myocytes (10). The expression of the ß3-receptor seems to be regulated in a tissue-specific manner, as lack of thyroid hormone resulted in up-regulation of this receptor in brown fat and down-regulation in white fat (11). On a post-receptor level, thyroid hormones regulate the signal transduction between the receptors and adenylate cyclase (7, 12). The demonstrated mechanism for this event is modulation of the steady state levels of specific G protein subunits, in particular the activity and abundance of the inhibitory G proteins, which couple antilipolytic receptors (6, 13). However, great care has to be taken when these findings in laboratory animals are extended to thyroid disorders in man. Species and tissue differences in adrenoceptor equipment as well as the use of clinically irrelevant study designs are some reasons why animal studies may differ from findings in man.
When previous studies of human thyrotoxicosis are summarized, it is still unknown whether this state in man is attributed to up-regulation of a specific ß-adrenoceptor subtype. Further, it is uncertain whether distal postreceptor changes near the hormone-sensitive lipase, catalyzing the rate-limiting step of the lipolysis, occur. The aim of this study was, therefore, to investigate the influence of thyroid hormones on the adrenergic regulation of lipolysis in abdominal sc adipocytes of hyperthyroid patients before and after antithyroid treatment, with special focus on the roles of ß1- and ß2-adrenoceptor subtypes and distal postreceptor events. Data from the hyperthyroid state were also compared to those from a group of sex-, age-, and body mass index-matched euthyroid controls.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
20/yr) were asked to participate in the study,
which included a fat biopsy on 2 different occasions. Initially, 14
patients (12 women and 2 men), with Grave’s disease but otherwise
healthy were included in the study and investigated before treatment.
All had undetectable serum TSH levels and highly elevated
concentrations of T3 and free T4 and a duration
of disease of at least 3–6 months at the time of the first
investigation (based on the history and laboratory findings provided by
the referring physicians). The patients received either radioiodine or
antithyroid drug, and after 4 weeks, additional therapy with
L-T4 (levothyroxine) was given. Data from these
subjects in the hyperthyroid state were compared to those from a
control group consisting of 18 age-, gender-, and body mass
index-matched volunteers (14 women and 4 men), all healthy and taking
no medication. Clinical data from all participants are presented in
Table 1
.
|
The subjects were investigated in the morning after an overnight fast. Height and body weight were measured. Venous blood samples were obtained for the determination of plasma catecholamine and thyroid hormone levels by the hospital’s routine chemistry laboratory. A sc fat biopsy (0.5–2 g) was obtained under local anesthesia from the abdominal region randomly to the right or the left of the umbilicus. The local anesthesia was given in a way that did not influence the function of the removed adipose tissue (14). It was not possible to remove larger pieces of adipose tissue because, first, all subjects were thin and, second, the tissue was hyperaemic in the hyperthyroid state.
Isolation of fat cells and lipolysis experiments
A piece of adipose tissue (150 mg) was first removed and
immediately frozen in liquid nitrogen for later analysis of
hormone-sensitive lipase. Then, fat cells were isolated from the stroma
by collagenase digestion according to the method of Rodbell (15). Fat
cells were carefully washed three times in Krebs-Ringer phosphate
buffer (pH 7.4) and filtered twice through a silk cloth to remove
traces of stroma and broken fat cells. Fat cell diameter, weight, and
volume as well as number of fat cells incubated were determined as
previously described (16).
The lipolysis assay, performed in all subjects, has previously
been described in detail (17). Briefly, a diluted suspension of fat
cells (5,000-10,000 cells/mL) was incubated for 2 h in
duplicate samples with air as the gas phase at 37 C in Krebs-Ringer
phosphate buffer (pH 7.4) supplemented with glucose (1 mg/mL), ascorbic
acid (0.1 mg/mL), and BSA (20 mg/mL) in the absence (basal) or presence
of increasing concentrations of different lipolysis agents. These were
the natural catecholamine norepinephrine, which acts on all
adrenoceptors present in human fat cells, i.e.
2-, ß1-, ß2-, and
ß3-adrenoceptors; the
ß2-adrenoceptor-selective agonist terbutaline; the
ß1-adrenoceptor-selective agonist, dobutamine; the
adenylate cyclase-stimulating agent, forskolin; and the
phosphodiesterase resistant cAMP analog, dibutyryl cAMP (dcAMP),
stimulating the protein kinase A-/hormone-sensitive lipase complex and
the selective 2-adrenoceptor agonist clonidine.
In the experiments with clonidine, the incubation buffer was
supplemented with adenosine deaminase (1 U/mL) to eliminate all traces
of adenosine, as this substance may interfere with the antilipolytic
effects that are mediated through 2-adrenergic
receptors. In a diluted incubation system, there is only minimal
leakage of adenosine, which does not influence the action of the
presently used lipolysis-stimulating drugs (17).
After incubation, an aliquot of the medium was removed, and glycerol, which was used as a measurement of the lipolysis rate, was analyzed using a bioluminescence method (18). The concentration-response curves showing glycerol release were analyzed for all lipolysis agents. A plateau was reached with each agent at the highest drug concentrations in all experiments. The maximum rate of glycerol release was calculated at the maximum effective concentration of the different agents (i.e. responsiveness). These values (with the basal lipolysis subtracted) for norepinephrine, dcAMP, and forskolin represent the maximum activation of lipolysis at the levels of all ß-receptors, adenylate cyclase, and the protein kinase-/hormone-sensitive lipase complex, respectively, as discussed in detail previously (16, 19). The responsiveness was also calculated for the selective adrenergic agonists dobutamine, terbutaline, and clonidine. However, for these agents, the main focus was made to evaluate adrenoceptor subtype sensitivity, as expressed by half-maximum effective concentration (EC50). The EC50 was determined by log-logit transformation and linear regression analysis of the dose-response curves, as previously described (20). At least six different concentrations of the selective adrenergic agonists were used, which covered the full concentration-response relationship in each experiment. The lipolysis rates were related to the number of incubated cells and expressed per cell number. Glycerol release is linear with time for at least 3 h in the absence or presence of lipolytic agents when abdominal sc fat cells are incubated under the present conditions (21).
Radioligand binding
The receptor binding studies were performed on isolated fat
cells as described in detail previously (16, 20). This assay was
performed in all 18 controls, but because of lack of adipose tissue, it
could only be performed in 10 of the entire group of 14 hyperthyroid
subjects and in 8 of the subset of 10 hyperthyroid patients who were
reinvestigated after antithyroid drug treatment. The nonselective
ß1- and ß2-adrenergic antagonist
[125I]cyanopindolol was used in saturation and
displacement experiments. Fat cells were incubated for 60 min in a
concentration of about 20,000 cells/mL at 37 C in a buffer composed as
described above, except that the albumin content was 5 g/L. In the
saturation experiments the fat cells were incubated with 10, 50, 100,
250, 500, and 750 pmol/L [125I]cyanopindolol. Nonspecific
binding (30–40%) was determined by the addition of propranolol (0.1
µmol/L) in parallel incubations. The cell-bound and free
radioactivities were separated by the addition of ice-cold saline and
vacuum-filtering through Whatman GF/C filters (Whatman, Clifton, NJ)
with a pore size of 1 µm, which retains intact fat cells but not
small cell fragments on the filter. The total maximum binding capacity
and ligand affinity were determined by linear regression analysis of
Scatchard plots (22). In the displacement experiments,
[125I]cyanopindolol binding (100 pmol/L) competed with
the highly selective ß2-adrenoceptor antagonist ICI
118,551 in 12 increasing concentrations
(10-11-10-4 mol/L). Nonspecific binding
(30%) was defined as the binding not displaced by 10-4
mol/L ICI 118,551 and was not different from nonspecific binding
determined using 0.1 µmol/L propranolol.
As the displacing ligand ICI 118,551 binds to ß2-receptors with high affinity and to ß1-receptors with low affinity, the displacement experiments gave shallow biphasic curves. A nonlinear least squares regression analysis of the displacement curves was performed (23). From the best-fitted two-site curve, it is possible to determine the proportion of binding sites with high (ß2-receptors) and low (ß1-receptors) affinity for the displacing ligand, respectively, as well as the binding affinities of ICI 118,551 to these two sites. The results of the saturation and displacement experiments taken together provide an estimate of the total binding capacity of ß1- and ß2-receptor binding sites, respectively, for each subject, which represents the ß-receptor subtype number. As discussed in detail previously (16, 19), ß3-adrenergic receptor binding cannot be detected under the present experimental conditions.
Assay of hormone-sensitive lipase activity
This assay was performed in 10 control subjects, 11 thyrotoxic patients, and 10 subjects reinvestigated after antithyroid therapy. It was conducted exactly as described previously (21). In brief, adipose tissue that had been stored in liquid nitrogen was homogenized at 4 C in 0.25 mol/L sucrose, 1 mmol/L ethylenediamine tetraacetate, 1 mmol/L dithiothreitol, and 20 mmol/L each of the protease inhibitors antipain and leupeptin. The homogenate was centrifuged at 100,000 x g, and the fat-free infranatant was recovered for analysis of maximum hormone-sensitive lipase activity using the diacylglycerol analog 1(3)-[3H]oleoyl-2-0-oleylglycerol as substrate (24). The substrate was obtained from the same source of production (Department of Medical and Physiological Chemistry, Lund University, Lund, Sweden) as in the original methodological studies (24, 25). The substrate for hormone-sensitive lipase has only one hydrolyzable ester bond at the 1(3) position. Therefore, the substrate and its hydrolysis products were not hydrolyzed by monoacylglycerol lipase, which is abundant in adipose tissue. Furthermore, under the present incubation conditions (pH 7.0 and no apolipoprotein CII present), lipoprotein lipase activity was negligible (24). As the phosphorylated and dephosphorylated forms of the enzyme have the same activity toward the substrate, only the total amount of activatable enzyme in the sample was measured (25). Hormone-sensitive lipase hydrolyzes tri- and diacylglycerols at a relative ratio of 1:10 (24). Therefore, the sensitivity of the assay was enhanced by the use of a diacylglycerol analog as substrate. All samples were incubated at 37 C for 30 min on one occasion. One unit of enzyme activity equals 1 mmol fatty acid produced/min at 37 C. Enzyme activity was related to the total protein concentration of the sample, which was measured using a commercial protein assay kit (BCA, Pierce Chemical Co., Rockford, IL). The enzyme activity and total protein concentration of the fat free infranatant were proportional to the wet weight of the tissue specimen when multiple samples from one subject were analyzed (r = 0.95; P < 0.005). The within-run coefficient of variation was 7%. The intraindividual coefficient of variation, examined by multiple samples of adipose tissue from one subject, was 11%.
Statistical analysis
Data are presented as the mean ± SE. The data were compared using Student’s paired and unpaired t tests and linear regression analysis.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
. All thyrotoxic patients reported weight reduction before
treatment; the mean decrease in body weight was about 5 ± 2 kg,
as judged by the patient’s own history. After treatment, there was a
significant rise in mean body weight by about 6 kg (P
< 0.005, by paired t test); in other words, the patients
had then approximately returned to their usual weight. After treatment,
there was also a significant increase in fat cell volume, of about 13%
(P < 0.05). Thyroid status did not influence the
levels of circulating catecholamines, which is in accordance with the
results of earlier studies (1).
Marked differences in lipolysis were found between hyperthyroid
and euthyroid subjects. When lipolysis was stimulated by the naturally
occurring catecholamine norepinephrine as well as by the
postreceptor-acting drugs forskolin and dcAMP, there was a pronounced
increase in the rate of lipolysis in the thyrotoxic patients compared
to that in the healthy controls (Fig. 1). These rates
were normalized and almost identical to those in the control group
after antithyroid therapy (Fig. 2).
|
|
). Antithyroid therapy almost
normalized responsiveness. As shown in Table 2, lipolysis induced by
dcAMP and forskolin was slightly higher in hyperthyroid subjects after
treatment compared to that in controls. However, when values from the
latter groups were compared using unpaired t test, no
significant difference was found.
|
2-adrenoceptors. Therefore, an increase
in receptor number is accompanied only by an increase in hormone
sensitivity, whereas an increased maximum lipolytic response is mainly
due to alterations at the postreceptor level (26). The evaluation of
these concentration-response curves was, therefore, expressed as a
percentage of the maximum lipolysis to enlighten right- or leftward
shifts in the curve, which reflects receptor sensitivity, as discussed
in detail previously (27). The concentration-response curves for
dobutamine and clonidine were almost superimposed when control and
hyperthyroid subjects were compared (Fig. 3), and they
were not influenced by antithyroid treatment (Fig. 4).
However, the curve for terbutaline was shifted to the left in
hyperthyroidism (Fig. 3) and normalized after antithyroid therapy (Fig. 4).
|
|
). As also shown in Table 3,
the EC50 for terbutaline was 1.2 log unit lower in
hyperthyroid than control subjects, which represents a more than
15-fold difference in sensitivity. The EC50 for terbutaline
was normalized after antithyroid therapy, whereas the effect of
clonidine was not affected by thyroid status, with no observed changes
in EC50 values (Table 3) and an inhibition of basal
lipolysis of about 70% (Figs. 3 and 4).
|
, there was a significant
up-regulation of the ß2-receptors in thyrotoxicosis.
The maximum radioligand binding capacity for this receptor in the
thyrotoxic state was more than 300% higher before compared to after
treatment and compared to healthy controls (P < 0.005
or less by paired and unpaired t tests). A 30–40% increase
in the number of ß1-adrenoceptors occurred during the
disease, but this difference was not statistically different.
ß1- and ß2-adrenoceptor subtype affinities
were not altered by hyperthyroidism (data not shown). All Scatchard
curves obtained before and after treatment were linear, and there was
no difference in [125I]cyanopindolol binding affinity
between the investigations (data not shown). To further characterize postreceptor mechanisms, measurements of hormone-sensitive lipase activity were performed. The enzyme activity, expressed as milliunits per mg protein, was 1.76 ± 0.25 in the entire group of thyrotoxic patients before treatment and 1.47 ± 0.22 in the control group (P = 0.4, by unpaired t test). In the group of thyrotoxic subjects who were investigated twice, the values were 1.84 ± 0.27 before and 1.46 ± 0.29 after (P = 0.11, by paired t test) treatment, respectively.
The possible influence of changes in body weight and fat cell size on the changes in lipolysis were investigated. The net differences in lipolytic responsiveness, ß2-adrenoceptor binding and terbutaline EC50 dependent variables, and fat cell size as well as body weight (independent variables) were calculated. Independent and dependent variables were compared by linear regression analysis. No significant relationship between these variables was obtained (r = -0.2 to 0.2).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The present results are different from what has been previously observed in studies of experimental hyperthyroidism in laboratory animals. When all animal experiments are considered together, it appears that the interactions between thyroid hormones and catecholamine-induced lipolysis are located at the ß1- and ß3-adrenoceptors, adenylate cyclase, and G proteins (6, 7, 8, 9, 10, 11, 12, 13, 28).
Because of the severity of the symptoms associated with naturally
occurring human thyrotoxicosis, detailed studies on lipolysis in this
condition are often not feasible. Little is known, therefore, about the
adrenergic regulation of lipolysis in human hyperthyreosis.
However, an increase in the total number of ß-adrenoceptors
(ß1 plus ß2) (2, 29), unaltered function of
the 2-receptor (29), and enhancement of the lipolytic
response to catecholamines (30) have been demonstrated in gluteal fat.
Human hyperthyroidism has also been associated with decreased activity
of the phosphodiesterase enzyme (3), which may elevate cAMP and thereby
activate lipolysis at the postreceptor level.
The present findings of the increased ability of norepinephrine to stimulate lipolysis in fat cells in untreated hyperthyroidism are in accordance with earlier observations. However, divergent from previous studies in thyrotoxic animals (7, 9, 10), we here demonstrate a selective enhancement of the ß2-adrenoceptor subtype function. This was indicated by a more than 15-fold increase in sensitivity for the ß2-receptor agonist terbutaline and was further confirmed by radioligand binding, which revealed a 3-fold increase in ß2-adrenoceptor number in the hyperthyroid compared to the euthyroid state. The ß1-adrenoceptor, whether measured with radioligand binding or functionally with EC50 for dobutamine, was not significantly altered by the hyperthyroid state. The present data clearly show that the increased lipolytic responsiveness induced by norepinephrine as well as the enhanced ß2-adrenoceptor subtype function observed in the hyperthyroid state decrease after treatment to levels almost identical to those observed in the control group. Lipolysis induced by postreceptor-acting drugs was somewhat greater in the hyperthyroid patients after treatment compared to controls; however, the values did not significantly differ. One explanation for these slightly higher values in hyperthyroid subjects an average of 7 months after treatment might be that postreceptor pathways are not yet normalized, but they might also be explained by the small number of subjects compared in this group. In healthy individuals, lipolytic parameters are stable in longitudinal experiments, as discussed in detail previously (17, 31). Taken together, these findings strongly indicate that the observed abnormalities in adrenergic regulation in hyperthyreosis are due to the disease itself and do not reflect spontaneous changes.
The enhanced ß2-adrenoceptor expression could only in part explain the increased norepinephrine function. The augmented maximal lipolytic response to norepinephrine mirrors changes beyond as well as at or near the adrenoceptor level. A postreceptor alteration could be located at any step in the lipolytic cascade beyond receptor binding. In experiments with drugs acting at selective postreceptor levels, forskolin as well as dcAMP significantly increased the maximal glycerol response in the hyperthyroid state. The latter drugs enhanced lipolysis to the same extent, and as dcAMP is resistant to the phosphodiesterase enzyme, the data indirectly indicate that the most important changes in the post-receptor events probably not are located at the level of the phosphodiesterase enzyme as indicated by previous studies (3), but presumably reside in the lipolytic chain near the level of the hormone-sensitive lipase. They do not, however, seem to be due to variations in the maximum enzyme capacity of the hormone-sensitive lipase, as no differences could be demonstrated between the hyperthyroid and the euthyroid state in this respect. The regulation of hormone-sensitive lipase activity is not known in detail. The present assay used only measures the total amount of the enzyme and cannot separate the phosphorylated, active form from the dephosphorylated, inactive form (25). The discrepancies between lipolysis and enzyme data in the thyrotoxic state could be due to increased phosphorylation of the enzyme, i.e. changes could be located at the level of the cAMP-dependent protein kinase A. They could also be explained by other enzymes involved in the phosphorylation-dephosphorylation reactions of the hormone-sensitive lipase, which were not able to be measured here.
The existence of postreceptor as well as receptor alterations in
thyrotoxicosis is further strengthened by comparing maximum lipolytic
responses in Table 2. For norepinephrine, acting at the initial step in
the lipolytic cascade (i.e. receptors), there was a 300%
increase in the effect in the hyperthyroid state. For forskolin and
dcAMP (acting below receptors), the corresponding augmentation was only
about 30–60%. In an earlier study in gluteal fat in humans, dcAMP
exhibited similar effects in hyperthyroid and euthyroid subjects (2).
One explanation for the differences in results might be that gluteal
fat is far less lipolytic active than abdominal fat, which was used in
the present study, as previously discussed (17).
The antilipolytic effect of clonidine was similar before as well as
after antithyroid treatment. This normal function of the inhibitory
2-receptor pathway in the hyperthyroid state indicates
an absence of changes at the level of the inhibitory component of the G
protein (i.e. Gi). This indirect finding is in
contrast to the results of earlier studies in rodents (13), but
supports previous investigations in humans (29, 32).
One question is whether these in vitro data also have impact in vivo. Ligget et al. (33) found unchanged ß-adrenoceptor-mediated responsiveness to epinephrine in vivo in experimental thyrotoxicosis induced in healthy volunteers. However, they also observed no alterations in isoprenaline-stimulated cAMP production in vitro in gluteal adipocytes despite a 60% increase in the total number of ß-adrenoceptors. The discrepancy between this earlier study and the present one might be due to different study designs. In the study by Ligget et al., gluteal fat was investigated, and normal humans were studied before and during short term experimental thyrotoxicosis, inducing elevated T3 levels but decreased serum T4 levels. Our patients had a duration of thyrotoxic disease of 3–6 months, with markedly elevated serum levels of both T3 and T4. Furthermore, subjects with natural hyperthyroidism may differ in other important ways from those with experimental thyrotoxicosis. The clinical importance of our in vitro findings can, thus, only be determined by in vivo lipolysis studies in patients with established thyrotoxicosis. For ethical reasons, infusing catecholamines in naturally occurring thyrotoxicosis to study in vivo sensitivity was not possible. We initially tried to evaluate in vivo lipolysis during physical exercise on a bicycle. However, these studies were not continued because of difficulties in achieving a sufficient work load in most of the patients. Alternatively, it might be possible to study lipolysis by microdialysis; unfortunately, this method is not yet quantitative.
In this study, it was only possible to study adipose tissue from the sc abdominal region. One question is whether the present results also apply to other regional fat depots. As discussed above, gluteal fat seems to be metabolically less active in the hyperthyroid state. We cannot determine from the present results whether the well known differences in lipolytic response to catecholamines between sc and visceral fat are even more augmented in thyrotoxicosis. Unfortunately, visceral fat is not available for the present type of experiments for ethical reasons. With regard to lipolytic sensitivity, an earlier study demonstrated a strong relationship between ß2-adrenoceptor sensitivities in sc and omental fat (17). Taken together, regional variation in lipolysis regulation during hyperthyroidism cannot be excluded; however, concerning the overall fuel homeostasis, sc fat is of major interest, as it constitutes about 80% of the total fat depot in man. Another important question is the possible occurrence of changes in the expression of the ß3-adrenoceptor in human thyrotoxicosis. Little is known about the regulation of this receptor during thyroid hormone excess. Unfortunately, when the present study was initiated about 5 yr ago, no appropriate ß3-adrenoceptor drugs were available.
It is of interest to compare the present findings regarding the ß2-adrenoceptor with those of other studies in our laboratory using identical methods. Lipolytic catecholamine resistance, with corresponding variations in ß2-adrenoceptor expression and function, but no change in the ß1-adrenoceptor, has been demonstrated in abdominal sc adipocytes of apparently normal subjects, in obese women, and in men with the so-called insulin resistance syndrome (17, 16, 19). When considered together, the present and earlier data strongly indicate that catecholamine action at the receptor level in human sc abdominal fat cells is mainly regulated by the ß2-adrenoceptor subtype.
Thyrotoxicosis is a catabolic state, like, for example, starvation. The latter condition is also accompanied by increased catecholamine-induced lipolysis. However, the most prominent finding with adipocytes obtained during long term fasting is an increase in basal lipolysis (20), which, however, was not influenced by thyrotoxicosis.
In summary, we demonstrated that adrenergic regulation of lipolysis in hyperthyroidism in man is associated with alterations at both receptor and distal postreceptor levels. The former is indicated by a selective up-regulation of the ß2-adrenoceptor, and the latter mechanism involves an increased ability of cAMP to activate hormone-sensitive lipase, but not a change in the maximum enzyme capacity.
|
Acknowledgments |
|---|
hlén, Britt-Marie Leijonhufvud, and Catharina
Sjöberg is greatly appreciated. |
Footnotes |
|---|
Received June 27, 1996.
Revised August 20, 1996.
Accepted August 27, 1996.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
- and ß-adrenergic receptor
systems and adrenergic responsiveness. Endocr Rev. 4:378–388.[Abstract]
2- and ß-adrenergic receptor binding and action in
gluteal adipocytes from patients with hypothyroidism and
hyperthyroidism. Metabolism. 36:1031–1039.[CrossRef][Medline]
2-adrenergic activity is normal in patients
with thyroid disease. Clin Endocrinol (Oxf). 40:235–239.[Medline]
This article has been cited by other articles:
 |
|
 |
|
  J. Polak, C. Moro, E. Klimcakova, M. Kovacikova, M. Bajzova, M. Vitkova, Z. Kovacova, R. Sotornik, M. Berlan, N. Viguerie, et al. The atrial natriuretic peptide- and catecholamine-induced lipolysis and expression of related genes in adipose tissue in hypothyroid and hyperthyroid patients Am J Physiol Endocrinol Metab, July 1, 2007; 293(1): E246 - E251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Silva Thermogenic Mechanisms and Their Hormonal Regulation Physiol Rev, April 1, 2006; 86(2): 435 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. N. Mariash Thyroid Hormone and the Adipocyte J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5603 - 5604. [Full Text] [PDF]
|
|
|
|
|
|
M. Haluzik, J. Nedvidkova, V. Bartak, I. Dostalova, P. Vlcek, P. Racek, M. Taus, S. Svacina, S. Alesci, and K. Pacak Effects of Hypo- and Hyperthyroidism on Noradrenergic Activity and Glycerol Concentrations in Human Subcutaneous Abdominal Adipose Tissue Assessed with Microdialysis J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5605 - 5608. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-Y. Liu, J. J. Schultz, and G. A. Brent A Thyroid Hormone Receptor {alpha} Gene Mutation (P398H) Is Associated with Visceral Adiposity and Impaired Catecholamine-stimulated Lipolysis in Mice J. Biol. Chem., October 3, 2003; 278(40): 38913 - 38920. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. D. Riis, C. H. Gravholt, C. B. Djurhuus, H. Norrelund, J. O. L. Jorgensen, J. Weeke, and N. Moller Elevated Regional Lipolysis in Hyperthyroidism J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4747 - 4753. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Viguerie, L. Millet, S. Avizou, H. Vidal, D. Larrouy, and D. Langin Regulation of Human Adipocyte Gene Expression by Thyroid Hormone J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 630 - 634. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Kalderon, N. Mayorek, E. Berry, N. Zevit, and J. Bar-Tana Fatty acid cycling in the fasting rat Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E221 - E227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lönn, K. Stenlöf, M. Ottosson, A.-K. Lindroos, E. Nyström, and L. Sjöström Body Weight and Body Composition Changes after Treatment of Hyperthyroidism J. Clin. Endocrinol. Metab., December 1, 1998; 83(12): 4269 - 4273. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
