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Original Article |
Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital and Institute of Experimental Clinical Science, Aarhus University, Aarhus 8000, Denmark
Address all correspondence and requests for reprints to: Anne Lene Dalkjær Riis, Medical Department M, Aarhus University Hospital, DK-8000 Aarhus, Denmark. E-mail: anne.lene.riis{at}iekf.au.dk.
Abstract
Hyperthyroidism is characterized by increased levels of circulating free fatty acids (FFA) and increased lipid oxidation, but it is uncertain which regional fat depots contribute. The present study was designed to define the participation of femoral and abdominal fat stores in the overall stimulation of lipolysis in hyperthyroidism in the basal state and during insulin stimulation.
We studied nine women with newly diagnosed hyperthyroidism (HT) and after (euthyroidism, ET) medical treatment with methimazol and compared with eight control subjects (CTR). All subjects were studied in the postabsorptive state and during a 3-h hyperinsulinemic euglycemic clamp with microdialysis catheters sc in the abdominal and femoral adipose tissue.
Before treatment, patients had elevated circulating concentrations of triiodthyronine, FFA, and glycerol. Levels of interstitial glycerol (µmol/liter) in abdominal adipose tissue [485 ± 24 (HT), 226 ± 20 (ET) (P < 0.001), 265 ± 34 (CTR) (P < 0.001)] and in femoral adipose tissue [468 ± 41(HT), 245 ± 29 (ET) (P < 0.01), 278 ± 31(CTR) (P < 0.005)] were elevated in the basal hyperthyroid state, and these differences prevailed during the glucose clamp [230 ± 23 (HT), 113 ± 13 (ET) (P < 0.01), 132 ± 22(CTR) (P < 0.01) and 303 ± 39 (HT), 122 ± 15 (ET) (P < 0.01), 166 ± 21(CTR) (P < 0.01)].
These results suggest that femoral and abdominal adipose tissue contribute equally to the excessive rate of lipolysis in hyperthyroidism and that both tissues are resistant to the actions of insulin.
EXCESS OF THYROID hormones affects intermediary metabolism profoundly, and hypermetabolism, involving all major fuel sources, is a hallmark of hyperthyroidism (1). In the postabsorptive state, hyperthyroid patients have elevated levels of blood glycerol and ketone bodies (2), presumably due to increased lipolysis and ketogenesis (3, 4, 5). In addition, administration of thyroid hormones to healthy subjects increases the plasma concentration of lipid intermediates (6, 7), glycerol turnover (8), lipid oxidation (9), and splanchnic ketone body production after a glucose load (10). Decreased sensitivity to the antilipolytic effect of insulin has also been reported (11, 12, 13), although others have found unchanged insulin sensitivity in hyperthyroidism (14). The effects of hyperthyroidism on lipid metabolism in vivo has, however, only been studied in a compartment remote from adipose tissue, namely blood, and little is known about the fat compartments responsible for the increased lipolytic rate. Consequently, the present study was undertaken to examine the influence of hyperthyroidism on regional fat metabolism. This was accomplished by the use of microdialysis, which allows measurement of interstitial levels of metabolites, such as glucose, glycerol, urea, and lactate (15, 16) in situ in sc abdominal and femoral adipose tissue. Microdialysis involves continuous monitoring of changes of fluxes of a variety of compounds from interstitial fluid to the dialysate and has been used in a large number of tissues in the human body since it was first introduced (17). True equilibrium can be accomplished across the membrane, when low flow rates are used (18). Glycerol is released from adipose tissue after lipolysis of triacylglycerols to free fatty acids (FFAs). Thus, to the extent that tissue disposal rates are constant, the changes in interstitial glycerol concentration represents lipolysis because glycerol is only produced and not taken up by adipose tissue (19, 20, 21). Regional differences between the three major fat depots, lower body sc fat, upper body sc fat, and intraabdominal splanchnic fat, do exist; it is, for instance, well recognized that upper body sc and splanchnic fat constitute a major risk factor for cardiovascular disease. In addition, a number of studies have suggested regional differences in the metabolic response to hormones, such as catecholamines (22), GH (22), cortisol (23), and insulin (23, 24). It remains uncertain whether thyroid hormones affect regional fat metabolism differentially.
The current study was designed to define the metabolic role of sc adipose tissue in patients with hyperthyroidism and to assess whether there may be regional differences between rates of lipolysis in upper body and lower body sc fat.
Subjects and Methods
Subjects (Table 1
)
Nine women, aged 26–49 yr, with newly diagnosed Graves’ disease were studied before and after 2–3 months of medical treatment with methimazol, when biochemically euthyroid for at least 4 wk. All patients had TSH receptor antibodies greater than 2 IU/liter, indicating an autoimmune pathogenesis of the hyperthyroidism (Graves’ disease). An untreated control group of eight healthy women was studied once. All patients and control subjects gave their written informed consent after receiving oral and written information concerning the study according to the Declaration of Helsinki II. The Århus County Ethical Scientific Committee approved the study.
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Subjects were admitted to the Clinical Research Center the evening before the day of the examinations. The participants were requested not to perform major physical exercise and to consume a weight-maintaining carbohydrate-rich diet for the last 3 d before examination and to refrain from alcohol intake on the day before the investigation. The investigations were carried out in the morning after an overnight fast (10–12 h) without any caffeine consumption or cigarette smoking; only ingestion of tap water was allowed and the participants were placed in the supine position under thermo neutral conditions. One iv catheter (Viggo AB, Helsingborg, Sweden) was placed in an antecubital vein for infusions, another in the contralateral antecubital vein for venous samples and a third in a superficial vein draining a hand, which was heated in a box with an air temperature 65 C to provide arterialized blood. Indirect calorimetry (Deltatrac, Datex Instrumentarium Inc., Helsinki, Finland) was performed to assess energy expenditure and fat oxidation rates. Microdialysis catheters (CMA 60, Stockholm, Sweden) with a molecular cut-off of 20 kDa were placed sc in the abdominal and femoral adipose tissue, respectively, after anesthetization of the skin with 0.5 ml lidocaine 0.1% at the site of perforation of the skin. Immediately after positioning the catheters were perfused with physiological perfusion fluid (perfusion fluid T1, CMA; Na+: 147 mmol/liter, K+: 4 mmol/liter, Ca2+: 2.3 mmol/liter, Cl-: 156 mmol/liter, pH: 6, osmolality: 290 mosmol/kg) at a flow rate of 0.3 µl/min with the use of a portable pump (CMA 106). At this flow rate, recovery rates from the microdialysis catheter is close to 100% (18, 24). After an hour of calibration with perfusion of the microdialysis catheter, sampling was started at t = 120 min and continued until t = 360 min with 60-min intervals. The samples thus reflect the integrated level of interstitial metabolites during the preceding 60 min and observed changes in interstitial glycerol concentrations reflect lipolysis (19, 20, 21), because negligible amounts of glycerol are reused in adipose tissue. Subjects were studied in the postabsorptive state for 3 h and thereafter during a 3-h hyperinsulinemic euglycemic clamp (insulin infusion: 0.6 mU/kg·min) simulating the fed state. The interstitial concentrations of metabolites measured by microdialysis represent mean values of samples collected during the last 2 h of each investigation period. Blood samples from the postabsorptive period and the clamp were collected in triplicate and averaged during the last half hour of each study period, when steady state was accomplished. Anthropometrical measurements and whole body dual-energy x-ray absorptiometry (DEXA) scanning were performed to evaluate changes in body composition before and after treatment.
Blood flow measurements
Subcutaneous adipose tissue blood flow (ATBF) in the abdominal region was measured by the local 133Xe washout method (26). In brief, 3.7 megabecquerels (0.1 ml) 133Xe was injected into the sc area of interest, equivalent to a whole body radiation dose of 0.5 mSv. Disappearance of 133Xe was monitored with a 2 x 2-inch sodium iodide crystal detector (model 905) connected to a photo multiplier base (model 276) (EG&G Ortec, Wokingham, Berks, UK) covered by a cylindrical copper collimator and coupled to a multi channel Ace Mate (model 925) amplifier (EG&G Ortec). The system was connected to a computer for simultaneous sampling. The registration of the washout rate was started at least 30 min after the injection. ATBF was calculated as ATBF = k x 
x 100 (ml/100 g·min). The rate constant of the washout curve is k, and is the tissue to blood partition coefficient for 133Xe at equilibrium; counts were collected every minute and a straight line was fitted through the experimental points in a semi logarithmic diagram as a function of time. Experimental values of k were determined as the slope of the regression line during a specified T, where T is the time frame (min). The time interval was at least 15 min. was calculated as: = 0.22 x SFT + 2.99, where SFT is the skin fold thickness of the abdominal adipose tissue (26, 27).
Assays
Thyroid hormones (total T3 and total T4) and TSH were measured by immunofluorescent methods (Immulite, DPC, Los Angeles, CA). Free thyroid hormones thyroxin and triiodothyronine were measured by RIA (28, 29). The clinical diagnosis of diffuse toxic goiter (Graves’ disease) was confirmed by measurements of TSH receptor antibodies (Lumitest TRAK human, Brahms Diagnostica GmbH, Hennigsdorf, Berlin, Germany). Plasma glucose was measured immediately after sampling in duplicate on an autoanalyzer (Beckman Instruments, Palo Alto, CA) by the glucose oxidase method. Serum insulin was measured by ELISA using a two-site immunoassay (30). Serum FFAs were determined by a colorimetric method employing a commercial kit (Wako Chemicals, Neuss, Germany). Blood samples were deproteinized with perchloric acid for determination of glycerol, 3-hydroxybutyrate, and lactate by an automated fluorometric method (31). Plasma glucagon was measured by an RIA (32). An automated spectrophotometric kinetic enzymatic analyzer (CMA 600) was used for duplicate measurements of glycerol, glucose, urea and lactate in the microdialysate.
Statistical analysis
All the data were tested for normal distribution by P-P-plots, Q-Q-plots, histograms, and the Kolmogorov-Smirnov test using SPSS for Windows version 10.0 (SPSS, Inc., Chicago, IL). Depending on this either Student’s paired t test, Student’s unpaired t test, Wilcoxon signed ranks test for related samples, or Mann Whitney U test for unrelated samples were employed for comparisons. Results are expressed as mean ± SE of the mean (SE). P values under 5% were considered statistically significant.
Results
Clinical characteristics and energy expenditure (Tables 1
and 2)
Patients and controls were of comparable age and height; both before and after treatment patients tended to have lower body weight (P = 0.28 after treatment). In the hyperthyroid state, the patients had a 3- to 5-fold elevation of total and free T3, compared with after treatment, when T3 decreased to normal levels. In the hyperthyroid state, the patients exhibited tachycardia (resting pulse 100 vs. 68/min after treatment), increased EE (1993 vs. 1515 kcal/24 h after treatment) and a decrease in RQ, indicating preferential lipid oxidation. The patients gained an average of 5 kg of body weight during treatment, and DEXA scans suggested that this was due to proportional increments in fat and lean body mass, albeit only the increase in fat mass was statistically significant.
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)Circulating levels of glycerol were elevated during hyperthyroidism both in the fasting state (fasting glycerol: 101 ± 12 vs. 50 ± 5 µmol/liter, P = 0.01) and during the glucose clamp. FFA concentrations tended to be elevated during fasting (827 ± 80 vs. 588 ± 55 µmol/liter, P = 0.07) and were elevated during the clamp (121 ± 28 vs. 47 ± 13 µmol/liter, P = 0.04). Fasting levels of 3-hydroxybutyrate also tended to be elevated during hyperthyroidism (362 ± 89 vs. 97 ± 30 µmol/liter, P = 0.06), but during insulin stimulation the concentrations of 3-hydroxybutyrate were fully suppressed. Fasting levels of urea (data not shown), glucose and lactate were comparable in the two conditions.
Microdialysis (Table 3 and Fig. 1)
Microdialysis revealed elevated levels of interstitial glycerol in abdominal adipose tissue [485 ± 24 µmol/liter (hyperthyroid) vs. 226 ± 20 µmol/liter (euthyroid), P = 0.00016] and in femoral adipose tissue [468 ± 41 µmol/liter (hyperthyroid) vs. 245 ± 29 µmol/liter (euthyroid), P = 0.007] in the fasting state. During the clamp we also found significant differences in interstitial glycerol levels, in the abdominal adipose tissue [230 ± 23 µmol/liter (hyperthyroid) vs. 113 ± 13 µmol/liter (euthyroid), P = 0.002)] and in the femoral adipose tissue [303 ± 39 µmol/liter (hyperthyroid) vs. 122 ± 15 µmol/liter (euthyroid), P = 0.006]. During the clamp, the hyperthyroid patients had significant regional differences in interstitial glycerol concentrations (P = 0.03) with higher glycerol concentrations in the femoral than in the abdominal adipose tissue, perhaps indicating a peripheral relative resistance to the antilipolytic effect of insulin in hyperthyroidism. Lactate concentrations were higher interstitially in adipose tissue than in plasma in hyperthyroid patients before and after medical treatment both fasting and during the clamp. We did not detect any significant differences in interstitial concentrations of glucose, lactate, or urea, when comparing the patients before and after treatment.
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Control subjects had interstitial concentrations of glycerol similar to those measured in euthyroid patients and significantly decreased levels compared with those measured in hyperthyroid patients both in the basal state and during insulin stimulation. Adipose tissue blood flow was lower in control subjects compared with patients in the fasting state regardless of whether the patients were hyperthyroid or euthyroid. During the clamp, we found significant difference in ATBF between hyperthyroid patients and control subjects and a tendency for higher blood flow in euthyroid patients than in control subjects (P = 0.08).
Discussion
Our study was designed to determine the role of sc abdominal and femoral adipose tissue for the increase in whole-body lipolysis observed in hyperthyroidism. The main finding of the study is that hyperthyroidism leads to a proportional increase of close to 100% in interstitial concentrations of glycerol in both femoral and abdominal fat, suggesting that both fatty acid depots contribute equally. This effect was apparent in the fasting state as well as during insulin stimulation. In this context, it should be noted that baseline values for interstitial glycerol concentrations in the patients after treatment and in healthy controls observed in the present study correspond closely to the ones available in the literature (21), indicating that recovery rates from the dialysis catheters have been close to 100% (18, 33, 34).
The lipolytic effects of thyroid hormone are firmly established, and in thyrotoxic states elevation of circulating fatty acids constitutes the major metabolic fuel in that clinical situation (1, 35). We previously found that oxidation of lipids is responsible for more than 60% of the resting energy expenditure in hyperthyroid patients (1). It is also worthwhile to note that sc fat is the principal fat depot, constituting up to 80% of the total fat content in humans (36). In addition, Meek et al. (37) have shown that 85% of FFAs originate from nonsplanchnic tissues, predominantly sc fat. Whether the finding of apparent insulin resistance in peripheral lower body adipose tissue in hyperthyroidism is accidental, or reflects a genuine pathophysiological phenomenon requires further studies to determine. In general, peripheral fat is more sensitive to the antilipolytic actions of insulin than is upper body sc fat (37).
The mechanisms leading to increased lipolysis and lipid oxidation in hyperthyroidism are, however, poorly understood. It is unclear whether thyroid hormones directly stimulate lipolysis by augmenting the activity of the hormone-sensitive lipase (HSL) enzyme. Beylot et al. (38) have reported 3-fold increased whole body turnover rates for glycerol in thyrotoxic patients, compatible with stimulation of HSL. Interestingly, the authors also observed a less marked increment in FFA turnover; perhaps indicating increased intracellular adipocyte re-esterification (FFA/triacylglycerol cycling), which could contribute to the hypermetabolism. It is also possible that thyroid hormones act by increasing the lipolytic sensitivity to other hormones such as catecholamines and GH. In vitro studies have suggested that the sensitivity to catecholamines may be enhanced at both the receptor and postreceptor level (36, 39), including an increase in the number of ß2-adrenoceptors and an increased ability of cAMP to activate HSL. The interstitial glycerol concentrations, measured with microdialysis, reflect the HSL action in fat cells more closely than the lipoprotein lipase action on the capillary wall (16).
During the hyperinsulinemic clamp, interstitial concentrations of glycerol and circulating levels of glycerol and FFA remained higher in the hyperthyroid patients, indicating a decreased sensitivity to the antilipolytic effect of insulin in femoral and abdominal adipose tissue. This is in line with others who have found elevated concentrations of FFA and glycerol postprandially (7, 37) and elevated circulating glycerol levels during insulin stimulation in hyperthyroidism (6), and it corresponds well with in vitro findings (11). It should, however, be noted that we recorded 25% lower circulating insulin concentrations in the thyrotoxic patients (Table 2). This is in all probability due to increased insulin clearance as previously reported by some authors (14, 40, 41). Others, however, have reported unchanged insulin clearance rates in hyperthyroidism (6, 12). In this connection, it is noteworthy that lipolysis is exquisitely sensitive to insulin (42) and that the recorded insulin concentrations 5-fold above fasting levels imply that inhibition of lipolysis has been close to the maximal antilipolytic effect of insulin (43).
Lactate concentrations were higher interstitially in adipose tissue than in plasma in hyperthyroid patients before and after medical treatment both fasting and during the clamp compatible with the notion that lactate may be produced in adipose tissue at basal conditions and that the production may be stimulated by insulin (44). Nevertheless, it should be remembered that the concentrations in the circulation and interstitially were measured with two different methods, making direct comparisons problematic (45, 46).
Hyperthyroidism is a catabolic state with breakdown of both lean body mass and fat mass. The changes in body composition observed in our study are slightly different from those reported by Lönn et al. (47), as we found an increase in both fat mass and lean body mass measured by DEXA scanning after treatment, whereas the Swedish patients did not display any increase in fat mass during the first 3 months of treatment. The increase of fat mass averaged 1.2 kg after medical therapy in our patients.
As with all experiments, the present study has limitations. Microdialysis estimates flux-generating concentrations of a variety of compounds across a diminutive dialysis membrane and permits assessment of changes in interstitial concentrations of these compounds in various tissues (48, 49, 50). True (or quasi-true) equilibrium across the membrane is only accomplished with very low flow rates, as used in the present study (49). Under these circumstances, any increase in glycerol concentrations in the perfusate may be seen as a reflection of increased regional lipolysis, provided that local blood flow and glycerol clearance are not altered. It should thus be considered that any change in regional blood flow could alter the flux generating concentration gradients across the dialysis catheter. Subcutaneous ATBF was increased under conditions of hyperthyroidism in our patients. It has previously been reported that both hyperthyroidism (51) and euglycaemic hyperinsulinaemic clamp (52) lead to increases in adipose tissue blood flow. A high sc blood flow would be expected to wash out more glycerol from the interstitial space to plasma and thereby lower glycerol concentrations interstitially. Therefore, the interstitial concentrations of glycerol may underestimate ongoing lipolysis in hyperthyroidism to the extent that extracellular glycerol is being diluted by a high blood flow. It appears all the more striking that we observed more than a doubling of glycerol levels in the patients when hyperthyroid. Several studies have shown that the abdominal sc adipose tissue blood flow is higher than femoral ATBF (53, 54, 55). Whether this also is the case in hyperthyroid women is uncertain. Another reservation relates to the fact that the microdialysis technique involves assessment of glycerol—and not FFA—levels. It is therefore conceivable that the technique overestimates actual FFA release by failing to account for re-esterification of FFA to acylglycerols (38). Finally, it should be mentioned that the current techniques do not allow estimations of the metabolic conditions in visceral adipose tissue. As mentioned above, splanchnic fat contributes between 10 and 20% of whole body FFA flux (24).
In conclusion, we confirm that hyperthyroidism leads to increases in concentrations of circulating lipid intermediates and lipid oxidation. Our data strongly suggest that activation of lipolysis in sc adipose tissue of both the upper and lower body is a driving force behind these phenomena, as evidenced by the distinct increments in interstitial levels of glycerol in abdominal and femoral fat.
Acknowledgments
Roche Diagnostics generously supplied the microdialysis catheters and other utensils. Lone Svendsen and Iben Christensen are thanked for excellent technical assistance.
Footnotes
The study was supported by a grant from the Danish Health Research Council, Grant 9600822 (Aarhus University-Novo Nordisk Center for Research in Growth and Regeneration). The Aarhus University Research Fund and Musikforlæggerne Agnes og Knut Mørks Fond supported the study. Parts of this study were presented at the 12th International Thyroid Congress, Kyoto, Japan, 2000.
Abbreviations: ATBF, Adipose tissue blood flow; CTR, control subjects; DEXA, dual-energy x-ray absorptiometry; ET, euthyroidism; FFA, free fatty acids; HSL, hormone-sensitive lipase; HT, hyperthyroidism.
Received February 6, 2002.
Accepted July 1, 2002.
References
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