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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 8 3851-3858
Copyright © 2002 by The Endocrine Society

Original Article

Hyposomatotropism Blunts Lipolysis in Abdominally Obese Women

Madelon M. Buijs, Jacobus Burggraaf, Janneke G. Langendonk, Rik C. Schoemaker, Marijke Frölich, Jan-Willem Arndt, Adam F. Cohen, Johannes A. Romijn, Mariette T. Ackermans, Hans P. Sauerwein, A. Edo Meinders and Hanno Pijl

Department of General Internal Medicine (M.M.B., J.G.L., M.F., A.E.M., H.P.), Centre for Human Drug Research (J.B., R.C.S., A.F.C.), Department of Nuclear Medicine (J.-W.A.), and Department of Endocrinology (J.A.R.), Leiden University Medical Centre, Leiden 2300 RC, The Netherlands; and Department of Clinical Chemistry (M.T.A.), Laboratory of Endocrinology and Radiochemistry, and Department of Endocrinology and Metabolism (H.P.S.), Academic Medical Center, Amsterdam 1100 DD, The Netherlands

Address all correspondence and requests for reprints to: Madelon M. Buijs, Department of General Internal Medicine, Leiden University Medical Centre, C1-R39, P.O Box 9600, 2300 RC Leiden, The Netherlands. E-mail: . m.m.buijs{at}lumc.nl

Abstract

Abdominal obesity is associated with reduced 24-h plasma GH concentrations. It is unclear whether hyposomatotropism in abdominally obese humans is compensated by up-regulation of GH receptor sensitivity or causes less biological effect in target tissues. We, therefore, determined the responsiveness of adipose tissue to the lipolytic action of GH in abdominally obese (OB) and normal weight (NW) postmenopausal women.

An iv bolus of recombinant human GH or placebo was randomly administered to eight NW [body mass index (BMI): 22.2 ± 1.6 kg/m2] and eight abdominally OB (BMI: 32.1 ± 2.6 kg/m2) women. Lipolysis was measured by infusion of D5-glycerol and modeled as a function of plasma GH concentrations to describe adipose tissue responsiveness.

Similar plasma GH concentration peaks (~20 mU/liter) were achieved by GH injection in both groups. During placebo conditions, the average plasma GH level was significantly lower in OB compared with NW women (0.74 ± 0.52 vs. 2.08 ± 1.18 mU/liter, P = 0.023). Adipose tissue responsiveness, expressed as glycerol rate of appearance per kilogram of fat mass per unit plasma GH concentration was not different in both groups (NW: 1.06, OB: 0.68, P > 0.05).

These results suggest that hyposomatotropism in abdominally obese individuals is not compensated by increased adipose tissue responsiveness to GH bio-action and, therefore, blunts lipolysis in these individuals.

ABDOMINAL OBESITY IS associated with reduced 24-h plasma GH concentrations (1, 2). The (patho) physiological impact of this phenomenon is unknown. Chronic hyposomatotropism in obese humans may up-regulate GH receptor number and/or sensitivity, as tends to occur in physiological systems to compensate for diminished ligand availability. Alternatively, hyposomatotropism of obesity may translate less or even deficient biological effects of GH to target tissues of (abdominally) obese humans. It seems important to unravel this issue because GH deficiency as a sequel of pituitary disease, is accompanied by a considerably increased risk for (type 2) diabetes mellitus (DM2) and cardiovascular disease (3). Thus, if hyposomatotropism translates less biological effects of GH to target tissues of abdominally obese humans, it may contribute to their well known tendency to develop these disorders.

Various observations reported in the literature argue in favor of either concept. Increased GH sensitivity is supported by the fact that obese children, despite being hyposomatotropic, do achieve normal final height (4). Moreover, plasma IGF-I and IGF-binding protein 3 (IGFBP-3) levels, both measures of GH bioactivity (5, 6), are normal in adult obese humans (7), despite reduced plasma GH levels. However, in favor of the alternative hypothesis, upper-body obese humans, typically characterized by profound hyposomatotropism, have numerous metabolic features in common with GH deficient patients. For example, both conditions are associated with insulin resistance, hypercholesterolemia, reduced high density lipoprotein cholesterol levels and hypertension (3, 8), and, as in GH-deficient individuals, GH substitution ameliorates the metabolic profile in abdominally obese humans (9).

The classic effect of GH is promotion of linear growth, but throughout life GH also has important metabolic effects. For instance, it promotes lipolysis by both direct and indirect actions on adipocyte physiology (10). This study aimed to determine adipocyte responsiveness to the lipolytic action of GH in abdominally obese (OB) vs. normal weight (NW) women. Our null hypothesis entailed equal responsiveness in both groups, which, if not rejected, would imply that hyposomatotropism blunts (GH-mediated) lipolysis in abdominally obese humans. To test our hypothesis, we conducted a placebo-controlled study, in which we administered a dose of recombinant human GH (rhGH) iv to mimic physiological plasma GH pulse concentrations in abdominally OB postmenopausal women and in NW controls matched for age and sex. GH-induced lipolysis was estimated by mathematical modeling of the relationship between the plasma GH concentration and the glycerol rate of appearance (Ra) as determined by a stable isotope technique.

Materials and Methods

Subjects

Eight NW (BMI <25 kg/m2 and fat mass <35%) and eight OB (BMI >29 kg/m2 and fat mass >40%) postmenopausal (FSH levels >20 U/liter) women participated in the study (Table 1Go). The subjects were healthy, nonsmoking, and not taking any medication (including hormonal replacement therapy). They all had plasma cholesterol less than 6.5 mmol/liter, fasting triglycerides less than 4.0 mmol/liter and HbA1C less than 6.7%. The subjects were weight stable and did not exercise for more than 3 h/wk. During the 3 d preceding the study, the participants consumed a weight-maintaining diet containing at least 250 g carbohydrate. The study protocol was approved by the Medical Ethics Committee of Leiden University Medical Centre. Subjects were recruited using the Centre for Human Drug Research volunteer pool and using advertisements in the local media. Written informed consent was obtained from all participants.


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  		Table 1. Subject characteristics ± SD

 
Experimental procedures

The study comprised two occasions and was performed in a randomized, placebo controlled and double-blind fashion. An interval of at least 5 d separated the two occasions. After a 10-h overnight fast, the subjects were admitted to the Clinical Research Unit of the Centre for Human Drug Research. They remained fasted in a semirecumbent position until the end of the occasion and were allowed to drink only water. The subjects emptied their bladder just before the start of procedures. All urine produced during the study (11 h) was collected for determination of catecholamine and creatinine excretion.

A cannula was inserted into an antecubital vein to infuse isotope tracers and GH or placebo. Another catheter was placed into a dorsal hand vein of the contralateral arm, and this hand was kept in a thermoregulated (60 C) box to sample arterialized venous blood (11). The catheter was kept patent by infusion of NaCl 0.9% (30 ml/h). At 1000 h, a primed (1.6 µmol/kg), continuous (0.11 µmol/kg/min) iv infusion of [1,1,2,3,3-2 H5]-glycerol (or D5-glycerol, 98% atom percent excess; Cambridge Isotope Laboratories, Andover, MA) dissolved in saline 0.9% was started and continued for 8 h, using a calibrated Sigma (St. Louis, MO) 6000 + pump (12). Exactly 60 min later, rhGH [0.195 + (0.005316*weight (in kg)] x 400 mU; Pharmacia Corp., Peapack, NJ) in a 9-ml solution or placebo (NaCl 0.9%) was administered iv by hand in 2 min. This time-point was set at t = 0 h. The specific dose of rhGH was chosen to achieve comparable areas under the curve (AUCs) of 400 mU/liter x min in both NW and OB subjects, as this dose corrects for increased GH clearance with increasing body weight (based on data from Ref. 13).

Before isotope infusion (t = -66 min), a blood sample was obtained to determine background isotope enrichment. Three arterialized blood samples were obtained to determine basal lipid kinetics. Blood samples to estimate the lipolytic response to GH and placebo injection were drawn every 20 min from t = 20 to 420 min. Blood samples for plasma free fatty acids (FFA), insulin, and glucose concentrations were obtained every 20 min during the same timeframe. Plasma GH levels were determined every 10 min. Plasma IGF-I levels were determined additionally to GH at t = -66 and 360 min and IGFBP-3 concentrations only at t = -66 min.

Indirect calorimetry using a ventilated hood (Oxycon ß, Jaeger Toennies, Breda, The Netherlands) was performed during 30 min at t = -120, 120 min, and 240 min to estimate substrate oxidation rates (14).

On a separate day total body fat mass and total lean body mass (LBM) were assessed using dual energy x-ray absorptiometry (Hologic, Inc. QDR 4500, Waltham, MA) (15). The scanner had a coefficient of variation for body fat mass of 2.1% and for LBM of 1.0%.

Assays

Blood for total glycerol, tracer enrichment of glycerol and GH concentrations was collected in 2.7 ml Li-heparin tubes. FFAs were determined in blood collected in 1.2 ml EDTA tubes. Insulin and glucose were determined in 1.2 ml serum. All blood samples were collected in prechilled tubes and were kept on ice (except the serum tubes). They were centrifuged within 30 min of sampling (2000 x g at 4 C, during 10 min). Plasma, serum, and urine samples were stored at -40 C and transported on dry ice before assay.

Serum glucose and urinary creatinine were measured at the laboratory for clinical chemistry at Leiden University Medical Centre, using a fully automated Hitachi 747 (Hitachi, Tokyo, Japan) system. Serum insulin was assayed by RIA (Medgenix, Fleurus, Belgium) with a detection limit of 3 mU/liter. The interassay coefficient of variation was 3.8–8.0% over the concentration range of 12.5–94.5 mU/liter. Plasma GH was measured by time-resolved fluoroimmunoassay (Delfia, Wallac, Inc., Turku, Finland) specific for the 22 kDa GH, which was used as the standard (Genotropin, Pharmacia Corp.) as calibrated against the World Health Organization First International Reference Preparation, 80/505 (to convert µg/liter to mU/liter, multiply by 2.6). The limit of detection was 0.03 mU/liter. The intraassay coefficient of variation varied from 1.6 to 8.4% in the assay range from 0.26 to 47 mU/liter, and the interassay coefficient of variation was 2.0–9.9% in the same range. The total plasma IGF-I concentration was measured by RIA (INCSTAR Corp., Stillwater, MN) after extraction and purification on octadecylsilica columns. The interassay coefficient of variation was less than 11%. The limit of detection was 1.5 nmol/liter. Plasma IGFBP-3 concentration was measured by RIA (Nichols Institute Diagnostics, San Juan Capistrano, CA). The interassay coefficient of variation was less than 6.8% at different concentrations. The limit of detection was 2.8 nmol/liter.

Catecholamines in urine were determined with an HPLC method followed by electrochemical detection. Plasma FFA was measured using an enzymatic colorimetric assay kit (Roche Molecular Biochemicals, Mannheim, Germany). Plasma glycerol concentrations and stable isotope tracer enrichment were determined in a single analytical run, using gas chromatography coupled to mass spectrometry (Hewlett-Packard Co., Palo Alto, CA) as described previously (16).

Calculations

Plasma hormone and substrate concentrations. Maximum GH concentrations in response to GH injection were analyzed to determine if similar GH peaks were achieved in both groups (as the lipolytic response to a GH pulse is dose dependent). In addition, GH AUCs (using the linear trapezoidal rule and 0 mU/liter as baseline) were calculated from t = –66 to 420 min to estimate total exposure to GH. Glycerol, FFA, glucose, and insulin were analyzed by calculating areas under the effect curves (AUECs) from t = 20 to 420. Subsequently, both AUCs and AUECs were divided by the corresponding time-span to obtain weighted average responses. Average pre-values for these values were calculated from t = -66 to -3 min. Absolute and percentage changes from these pre-values were calculated. To allow correction for differences in catecholamine exposure, urinary catecholamines released per micromole of creatinine (to correct for urine concentration) were determined in both groups from urine collected throughout the occasion. IGF-I was analyzed by comparing basal values with values obtained 6 h after GH or placebo administration.

Lipolysis. Glycerol concentration and enrichment data were used to calculate glycerol kinetics. Steele’s equation for nonsteady-state conditions adjusted for stable isotopes was used (17), as the isotopic steady-state was disrupted by the rhGH bolus injection. The effective volume of distribution of glycerol was assumed to be 14 liters in all subjects (18). In case of glycerol, it is not necessary to compensate for nonuniform mixing (18). Therefore, the correction factor p of the nonsteady-state equation was assumed to be equal to 1. Total lipolysis and glycerol Ra per kilogram of body fat were analyzed by calculating AUECs (mean lipolytic rates) from t = 20 to 420 min. Mean pre- or basal values for lipolysis were calculated from t = -6.5 to 8.5 min. Absolute and percentage changes from these pre-values were calculated as well.

Adipose tissue responsiveness. To determine adipose tissue GH responsiveness, the influence of GH on lipolysis was investigated using pharmacokinetic-pharmacodynamic modeling. The details of the modeling procedure are described elsewhere (19). In short, such an analysis produces a model describing glycerol Ra as a function of transferred plasma GH concentrations. Plasma GH, D5-glycerol, and total glycerol concentrations were used to build the model. D5-glycerol concentrations were used to estimate glycerol distribution and elimination. Glycerol Ra was described as the sum of two parts. The first part described basal glycerol Ra, which was assumed to be constant over the day. The second part comprised GH-dependent glycerol Ra, describing the change in glycerol Ra as a function of transferred GH effect levels. Because GH bio-action requires induction of a cascade of biochemical changes (20), resulting in both a delay in onset and an extended duration of effect, two sequential effect compartments were used to translate GH into glycerol Ra (21). The postulated GH concentrations of the second effect compartment were translated into GH-dependent glycerol Ra using a proportionality factor. This factor is a measure of adipose tissue responsiveness, as it estimates the increase in glycerol release per unit GH effect concentration. All glycerol Ra estimates were corrected for adipose tissue mass. A paired analysis was performed, where adipose tissue responsiveness was assumed similar for an individual on both occasions. The delay-model and physiological significance of the effect compartments is schematically presented in Fig. 1Go.



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  		Figure 1. Schematic representation of the model describing the delay between plasma GH and resulting change in lipolysis.

 
Model parameters were estimated using nonlinear mixed effect modeling (NONMEM). This methodology simultaneously analyzes all data from all subjects while still allowing subjects to be different. Average population parameters are estimated and estimates of variability in parameters between subjects are obtained. Based on these population parameters and the individual measurements, individual parameter estimates (empirical Bayes estimates) can be generated (22).

Estimates of differences between NW and OB groups were made for basal glycerol Ra and GH-dependent glycerol Ra. Parameters were estimated using first order conditional estimation with NONMEM software (version V, NONMEM Project Group, University of San Francisco, San Francisco, CA) where glycerol and D5-glycerol data were estimated simultaneously using an additive residual error model.

Statistics

Calculations were performed using SPSS, Inc. for Windows version 10.0.7 (SPSS, Inc., Chicago, IL).

Data are presented as mean ± SD (unless specified otherwise). Statistical analysis of between-group differences (NW vs. OB subjects) was done by the unpaired Student’s t test. Within-group differences (GH vs. placebo) were analyzed by the paired Student’s t test. A P value of less than 0.05 was considered statistically significant.

Results

Plasma GH concentrations

Plasma GH peak values and AUC in response to GH injection were similar in both groups (peak values: NW: 20.3 ± 4.3 mU/liter, OB: 19.8 ± 6.9 mU/liter, P = 0.859, Fig. 2Go). In contrast, the average plasma GH concentration during placebo conditions was significantly higher in NW than in OB women (2.08 ± 1.18 vs. 0.74 ± 0.52 mU/liter, P = 0.023).



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  		Figure 2. Plasma GH ± SD concentration after GH (A) and placebo (B) injection in normal weight (closed circles) and obese (open circles) subjects.

 
Lipid intermediates and lipolysis

Basal glycerol levels were significantly lower in NW than in OB subjects, whereas basal FFA concentrations were similar in both groups (glycerol: 57.7 ± 7.8 vs. 73.2 ± 15.4 µmol/liter, P = 0.028; FFA: 348 ± 46 vs. 307 ± 81 µmol/liter, P = 0.247). Plasma glycerol and FFA concentration over time profiles are shown in Fig. 3Go. Average plasma glycerol and FFA concentrations increased to a similar extent in both groups in response to GH administration. In NW women, these increases were similar to those in placebo conditions. In OB women, however, rhGH administration elicited significantly larger increments of both plasma glycerol and FFA concentrations than placebo injection did (Table 2Go).



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  		Figure 3. Average ± SD glycerol and FFA concentrations in NW (squares) and OB (circles) subjects. Closed squares and circles represent profiles after GH administration, open squares and circles after placebo administration.

 

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  		Table 2. Changes in lipolytic and additional parameters (mean ± SD)

 
Basal lipolytic rate was significantly higher in OB than in NW subjects (171 ± 34 vs. 128 ± 35 µmol/min, P = 0.025). However, if expressed per kilogram of fat mass, glycerol Ra was higher in NW compared with OB subjects (7.0 ± 1.5 vs. 4.7 ± 0.5 µmol/kg x min, P = 0.003). Exogenous GH administration induced a similar increment of total lipolysis (P = 0.994) in both groups. In contrast, the GH induced glycerol Ra per kilogram of fat mass tended to be less in OB compared with NW subjects (P = 0.194, Table 2Go). In NW subjects, lipolysis changed similarly in response to GH and placebo injections. In OB women, total lipolysis and lipolysis per kilogram of fat increased significantly more after GH than after placebo administration (P = 0.022 and 0.027, respectively, Table 2Go).

Adipose tissue responsiveness

Individual D5-glycerol concentration profiles showed almost constant levels over the time-period studied. Using these profiles together with plasma GH and total glycerol concentrations, it was possible to build a pharmacokinetic-pharmacodynamic model, predicting basal glycerol Ra and GH-dependent glycerol Ra as a function of GH effect concentrations (adipose tissue GH responsiveness). Visual inspection showed satisfactory associations between model-predicted lipolysis and calculated glycerol Ra by applying Steele’s equation (Fig. 4Go). NONMEM estimates for the model are listed in Table 3Go. Glycerol Ra per kilogram of fat mass was significantly lower in OB compared with NW subjects (NW: 6.7 vs. OB: 4.1 µmol/kg·min, OB-NW: -2.6 µmol/kg·min with 95% confidence interval: -3.7 to -1.5 µmol/kg·min). Although adipose tissue responsiveness for GH induced lipolysis tended to be reduced in OB compared with NW subjects, the difference did not reach statistical significance (NW: 1.06 vs. OB: 0.68, OB-NW: -0.38 with 95% confidence interval: -0.97 to 0.20).



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  		Figure 4. Average ± SD glycerol Ra per kilogram of fat as predicted by the model (solid lines) and by applying the Steele’s equations to the raw data in NW (squares) and OB (circles) subjects. Closed squares and circles represent profiles after GH administration, open squares and circles after placebo administration.

 

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  		Table 3. Glycerol Ra/kg body fat mass estimates

 
Additional effects

Basal plasma IGF-I and IGFBP-3 levels in NW subjects were similar to those in OB subjects (IGF-I: 20.2 ± 5.1 vs. 20.2 ± 3.1 nmol/liter; IGFBP-3: 71.6 ± 25.6 vs. 73.0 ± 28.1 nmol/liter). IGF-I slightly increased in response to GH injection in NW subjects, whereas it did not change in OB individuals. Plasma IGF-I tended to decrease in placebo conditions in both groups. However, none of these effects reached statistical significance (Table 2Go).

Baseline insulin levels were higher in OB than in NW subjects (19.0 ± 8.2 vs. 8.3 ± 3.0 mU/liter, P = 0.008). In OB subjects, serum insulin levels decreased significantly less after GH than after placebo administration (GH: -18.0 ± 7.7%, saline: -26.3 ± 9.7%, P = 0.008, Table 2Go). In NW subjects, insulin concentrations declined similarly during both conditions (P = 0.832). Basal glucose levels were higher in OB than in NW subjects (5.7 ± 0.3 vs. 5.2 ± 0.3 mmol/liter, P = 0.003). In OB subjects, glucose levels decreased, but without treatment-induced differences (Table 2Go). Adrenaline, noradrenaline and dopamine concentrations in urine did not differ between OB and NW groups, neither following GH, nor after placebo administration (data not shown).

Basal lipid oxidation rates per kilogram of LBM were similar in both groups. In contrast, basal carbohydrate oxidation rates per kilogram of LBM were higher in NW compared with OB women (5.25 ± 0.67 mg/kg·min vs. 4.34 ± 0.98 mg/kg·min, P = 0.049). In placebo conditions, lipid oxidation rates increased and carbohydrate oxidation rates decreased during the day in both groups. GH administration did not affect these oxidation rates in either group (lipid: NW: P = 0.653, OB: P = 0.663, carbohydrate: NW: P = 0.849; OB: P = 0.551). The changes that we observed during the day were probably brought about by fasting.

Discussion

The purpose of this study was to investigate in vivo adipose tissue responsiveness to the lipolytic action of GH in abdominally obese women, who are typically characterized by profound hyposomatotropism. We aimed to establish whether the well-known reduction of circulating GH concentrations in these women has metabolic significance or merely reflects a distinct fine-tuning of ligand-receptor interaction of the somatotropic axis. To this end, exogenous GH was administered iv to mimic a physiological plasma GH concentration pulse of equal height in abdominally obese and normal weight postmenopausal women. GH induced lipolysis was estimated by mathematical modeling of the time-delayed relation between the plasma GH concentration and the glycerol rate of appearance.

The results show that the increase of glycerol release per kilogram of fat and per unit GH is similar in both groups of subjects. This indicates that adipose tissue of abdominally obese and normal weight women is equally sensitive to the lipolytic action of GH. In addition, the data confirm previous literature indicating that circulating GH levels are considerably reduced in abdominally obese women (1, 2). It seems reasonable to infer that reduced plasma GH levels in the face of normal adipocyte responsiveness to GH action will translate diminished biological effect of GH to adipose tissue and thereby blunt lipolysis in abdominally obese women.

The mathematical technique we employed to estimate adipose tissue responsiveness to the lipolytic action of GH is a novel tool in endocrine physiology. The method is generally accepted in pharmacology (23), and animal experiments have shown that this approach can be a feasible tool to describe drug-induced lipolysis (24). Mathematical modeling of the intricate relationship between plasma GH concentrations and estimated lipolytic rates was a prerequisite for proper investigation of our hypothesis. A placebo control study was necessary to specifically judge the effects of GH on lipolysis, as many other endocrine cues that tend to differ between obese and normal weight humans (e.g. insulin, cortisol) also govern lipolyis. By subtracting the lipolytic response to placebo injection from that to GH administration, we were able to specifically infer the effects of administered GH on lipolysis. However, simple comparison of the difference in lipolytic response to GH vs. placebo injection as a measure of GH bio-action in obese and normal weight subjects would have been strongly flawed by the fact that the spontaneous plasma GH levels in placebo conditions were considerably higher in normal weight women (Fig. 2Go). In fact, the average plasma GH concentration was similar during GH intervention and placebo conditions in normal weight subjects (as endogenous GH secretion was restrained by exogenous GH administration), which may be the main reason for the lack of difference in lipolytic rate between the occasions in these women (Table 2Go). Modeling lipolysis as a function of the plasma GH concentration fully obviates this analytical difficulty. Importantly, in both groups and irrespective of treatment applied, the model-dependent estimates of lipolysis were strikingly similar to the estimates generated by applying Steele’s technique, whereas the last approach does not model the relationship between stimulus (i.e. GH) and glycerol Ra. This underscores the success of the modeling exercise and, therefore, supports the reliability of the model-estimates of proportionality or GH responsiveness factors.

It seems important to emphasize that our approach estimates the effects of a physiological plasma GH pulse on lipolysis within the biological context of normal weight and obese humans. Thus, other endocrine and metabolic effects of injected GH, which subsequently may have affected lipolysis, all impact our estimation of GH action. Therefore, our proportionality factors are not a measure of responsiveness of adipocytes per se, but rather estimate adipose tissue responsiveness in a holistic physiologic context. In this respect, it is noteworthy that the decline of plasma insulin levels was slightly blunted during GH administration in obese subjects only (whereas other cues remained stable in both groups, i.e. catecholamines, IGF-I).

Only one previous study examined the metabolic effects of exogenous GH administration in obese and normal weight humans. Seng et al. (25) did not detect differences in plasma FFA, glycerol, glucose, and insulin concentrations in response to a single im injection of GH in obese vs. normal weight subjects, which is in keeping with our results. As far as we are aware, there is no in vitro data comparing adipocyte sensitivity to GH bio-action in (abdominally) obese vs. normal weight humans available to date.

Hyposomatotropism in abdominally obese humans may serve to dampen lipolysis to protect against the untoward effects of elevated plasma FFA concentrations. Increased FFA flux can damage pancreatic ß-cells (26) and reduce insulin sensitivity of skeletal muscle (27) and liver (28). Thus, diminution of FFA flux via reduction of the plasma GH concentration in the face of normal tissue responsiveness to GH action may constitute a useful adaptation to enlarged fat stores. Accordingly, our data show that lipolysis per unit of fat mass is blunted in obese women. However, in spite of this putative adaptive mechanism, total lipolysis was higher in obese than in normal weight subjects. This may indicate that the protective strategy is not foolproof, maybe to prevent deficient FFA availability as a fuel for the enlarged LBM of obese individuals.

Unfortunately, this useful neuroendocrine adaptation to enlarged fat stores may also have adverse metabolic sequelae. The other metabolic actions of GH are numerous. It increases basal metabolic rate (29), inhibits lipoprotein lipase activity (30), promotes protein synthesis (31), and stimulates cholesterol removal from the circulation by activating low density lipoprotein receptors (32). Moreover, GH plays a role in the regulation of fibrinolysis (33) and it modulates the immune system (34). This study did not examine any of these particular actions of GH and, therefore, we cannot be sure that the signaling pathways governing these processes are not up-regulated in obesity. However, abdominally obese humans have some clinical features that might be explained by GH deficiency. Both syndromes are distinctly associated with combined hyperlipidemia (35) and a procoagulant and proinflammatory plasma profile (36, 37, 38, 39). In GH-deficient adults, GH therapy ameliorates their unfavorable cardiovascular risk profile (38, 33, 40) and reduces concomitant atherosclerotic changes of the vascular wall (41, 42). Therefore, diminished GH bioactivity may be involved in the pathogenesis of cardiovascular disease in abdominal obesity.

If abdominal obesity is indeed accompanied by deficient biological effect of GH, why is it that IGF-I levels are usually normal in obese adults, and why do obese children achieve a normal height? This is probably because IGF-I production by the liver is governed by other factors than GH and/or through other GH signaling pathways. For example, insulin can stimulate hepatic IGF-I production (43, 44), and, therefore, obesity associated hyperinsulinemia may explain the normal IGF-I values. Circulating IGF-I levels have little relevance for linear growth, as the effects of GH on growth are almost exclusively mediated by locally produced IGF-I (45). It is conceivable that GH has differential effects on lipolysis and IGF-I production in bone tissue. Moreover, hyperinsulinemia reduces IGFBP-1 concentrations. This will increase biologically active free IGF-I levels (46), which may contribute to the normal height of obese children.

In conclusion, the present study indicates that adipose tissue responsiveness to the lipolytic action of GH is similar in abdominally obese and normal weight women. In addition, it confirms the well established notion that abdominal obesity is associated with hyposomatotropism. Reduced circulating GH levels in the face of normal adipose tissue responsiveness dampens lipolysis in abdominally obese humans, which may reflect an adaptive mechanism to prevent the deleterious effects of increased FFA flux from enlarged fat stores. However, as an adverse sequel, hyposomatotropism in abdominal obesity potentially contributes to the development of an unfavorable risk profile for cardiovascular disease.

Acknowledgments

The excellent technical assistance of Eric Gribnau and Trea Streefland is greatly appreciated. We thank Pharmacia Corp. (Peapack, NJ) for its generous gift of rhGH for this study.

Footnotes

Abbreviations: AUC, Area under the curve; AUECs, areas under the effect curves; BMI, body mass index; FFA, free fatty acid; LBM, lean body mass; NONMEM, nonlinear mixed effect modeling; NW, normal weight; OB, abdominally obese; Ra, rate of appearance; rhGH, recombinant human GH.

Received January 16, 2002.

Accepted May 6, 2002.

References

  1. Vahl N, Jorgensen JO, Skjaerbaek C, Veldhuis JD, Orskov H, Christiansen JS 1997 Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults. Am J Physiol 272:E1108–E1116
  2. Pijl H, Langendonk JG, Burggraaf J, Frolich M, Cohen AF, Veldhuis JD, Meinders AE 2001 Altered neuroregulation of GH secretion in viscerally obese premenopausal women. J Clin Endocrinol Metab 86:5509–5515[Abstract/Free Full Text]
  3. Boer Hd, Blok GJ, van der Veen EA 1995 Clinical aspects of growth hormone deficiency in adults. [Review]. Endocr Rev 16:63–86[CrossRef][Medline]
  4. Vanderschueren-Lodeweyckx M 1993 The effect of simple obesity on growth and growth hormone. [Review]. Horm Res 40:23–30[Medline]
  5. Daughaday WH, Rotwein P 1989 Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations. Endocr Rev 10:68–91[Abstract]
  6. Blum WF, Ranke MB, Kietzmann K, Gauggel E, Zeisel HJ, Bierich JR 1990 A specific radioimmunoassay for the growth hormone (GH)-dependent somatomedin-binding protein: its use for diagnosis of GH deficiency. J Clin Endocrinol Metab 70:1292–1298[Abstract]
  7. Nam SY, Lee EJ, Kim KR, Cha BS, Song YD, Lim SK, Lee HC, Huh KB 1997 Effect of obesity on total and free insulin-like growth factor (IGF)-1, and their relationship to IGF-binding protein (BP)-1, IGFBP-2, IGFBP-3, insulin, and growth hormone. Int J Obes Relat Metab Disord 21:355–359[CrossRef][Medline]
  8. Reaven GM 1995 Pathophysiology of insulin resistance in human disease. [Review]. Physiol Rev 75:473–486[Abstract/Free Full Text]
  9. Johannsson G, Marin P, Lonn L, Ottosson M, Stenlof K, Bjorntorp P, Sjostrom L, Bengtsson BA 1997 Growth hormone treatment of abdominally obese men reduces abdominal fat mass, improves glucose and lipoprotein metabolism, and reduces diastolic blood pressure [see comments]. J Clin Endocrinol Metab 82:727–734[Abstract/Free Full Text]
  10. Marcus C, Margery V, Kamel A, Bronnegard M 1994 Effects of growth hormone on lipolysis in humans. [Review]. Acta Paediatr Suppl 406:54–58[Medline]
  11. Abumrad NN, Rabin D, Diamond MP, Lacy WW 1981 Use of a heated superficial hand vein as an alternative site for the measurement of amino acid concentrations and for the study of glucose and alanine kinetics in man. Metabolism 30:936–940[CrossRef][Medline]
  12. Heijligenberg R, Romijn JA, Klein S, Endert E, Sauerwein HP 1997 Lipolytic sensitivity to catecholamines in patients with human immunodeficiency virus infection. Am J Clin Nutr 66:633–638[Abstract/Free Full Text]
  13. Langendonk JG, Meinders AE, Burggraaf J, Frolich M, Roelen CA, Schoemaker RC, Cohen AF, Pijl H 1999 Influence of obesity and body fat distribution on growth hormone kinetics in humans. Am J Physiol 277:E824–E829
  14. Simonson DC, DeFronzo RA 1990 Indirect calorimetry: methodological and interpretative problems [see comments]. [Review]. Am J Physiol 258:E399–E412
  15. Blake GM, Fogelman I 1997 Technical principles of dual energy x-ray absorptiometry. [Review] [83 refs]. Semin Nucl Med 27:210–228[CrossRef][Medline]
  16. Ackermans MT, Ruiter AF, Endert E 1998 Determination of glycerol concentrations and glycerol isotopic enrichments in human plasma by gas chromatography/mass spectrometry. Anal Biochem 258:80–86[CrossRef][Medline]
  17. Jensen MD, Heiling V, Miles JM 1990 Measurement of non-steady-state free fatty acid turnover. Am J Physiol 258:E103–E108
  18. Gastaldelli A, Coggan AR, Wolfe RR 1999 Assessment of methods for improving tracer estimation of non-steady-state rate of appearance. J Appl Physiol 87:1813–1822[Abstract/Free Full Text]
  19. Schoemaker RC, Buijs MM, Pijl H, Burggraaf J, Cohen AF 2002 Modeling the influence of growth hormone on lipolysis. J Pharmacokinet Pharmacodyn 29:157–170[CrossRef][Medline]
  20. Finidori J 2000 Regulators of growth hormone signaling. Vitam Horm 59:71–97[Medline]
  21. Holford NH, Sheiner LB 1981 Understanding the dose-effect relationship: clinical application of pharmacokinetic-pharmacodynamic models. Clin Pharmacokinet 6:429–453[Medline]
  22. Schoemaker RC, Cohen AF 1996 Estimating impossible curves using NONMEM. Br J Clin Pharmacol 42:283–290[CrossRef][Medline]
  23. Derendorf H, Lesko LJ, Chaikin P, Colburn WA, Lee P, Miller R, Powell R, Rhodes G, Stanski D, Venitz J 2000 Pharmacokinetic/pharmacodynamic modeling in drug research and development. J Clin Pharmacol 40:1399–1418[Abstract]
  24. van Schaick EA, de Greef HJ, Langemeijer MW, Sheehan MJ, IJzerman AP, Danhof M 1997 Pharmacokinetic-pharmacodynamic modelling of the anti-lipolytic and anti-ketotic effects of the adenosine A1-receptor agonist N6-(p-sulphophenyl)adenosine in rats. Br J Pharmacol 122:525–533[CrossRef][Medline]
  25. Seng G, Galgoti C, Louisy P, Toussain P, Drouin P, Debry G 1989 Metabolic effects of a single administration of growth hormone on lipid and carbohydrate metabolism in normal-weight and obese subjects. Am J Clin Nutr 50:1348–1354[Abstract/Free Full Text]
  26. Bjorklund A, Yaney G, McGarry JD, Weir G 1997 Fatty acids and ß-cell function. Diabetologia 40(Suppl 3):B21–B26
  27. Unger RH 1995 Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863–870[Abstract]
  28. Benthm L, Keizer K, Wiegman CH, de Boer SF, Strubbe JH, Steffens AB, Kuipers F, Scheurink AJ 2000 Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation. Am J Physiol Endocrinol Metab 279:E1286–E1293
  29. Salomon F, Cuneo RC, Hesp R, Sonksen PH 1989 The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 321:1797–1803[Abstract]
  30. Ottosson M, Vikman-Adolfsson K, Enerback S, Elander A, Bjorntorp P, Eden S 1995 Growth hormone inhibits lipoprotein lipase activity in human adipose tissue. J Clin Endocrinol Metab 80:936–941[Abstract]
  31. Cuneo RC, Salomon F, Wiles CM, Hesp R, Sonksen PH 1991 Growth hormone treatment in growth hormone-deficient adults. I. Effects on muscle mass and strength. J Appl Physiol 70:688–694[Abstract/Free Full Text]
  32. Rudling M, Norstedt G, Olivecrona H, Reihner E, Gustafsson JA, Angelin B 1992 Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proc Natl Acad Sci USA 89:6983–6987[Abstract/Free Full Text]
  33. Johansson JO, Landin K, Johannsson G, Tengborn L, Bengtsson BA 1996 Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults. Thromb Haemost 76:422–428[Medline]
  34. Buul-Offers SC, Kooijman R 1998 The role of growth hormone and insulin-like growth factors in the immune system. Cell Mol Life Sci 54:1083–1094[CrossRef][Medline]
  35. Terry RB, Wood PD, Haskell WL, Stefanick ML, Krauss RM 1989 Regional adiposity patterns in relation to lipids, lipoprotein cholesterol, and lipoprotein subfraction mass in men. J Clin Endocrinol Metab 68:191–199[Abstract]
  36. Sakkinen PA, Wahl P, Cushman M, Lewis MR, Tracy RP 2000 Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. Am J Epidemiol 152:897–907[Abstract/Free Full Text]
  37. Alessi MC, Bastelica D, Morange P, Berthet B, Leduc I, Verdier M, Geel O, Juhan-Vague I 2000 Plasminogen activator inhibitor 1, transforming growth factor-ß1, and BMI are closely associated in human adipose tissue during morbid obesity. Diabetes 49:1374–1380[Abstract]
  38. Kvasnicka J, Marek J, Kvasnicka T, Weiss V, Markova M, Stepan J, Umlaufova A 2000 Increase of adhesion molecules, fibrinogen, type-1 plasminogen activator inhibitor and orosomucoid in growth hormone (GH) deficient adults and their modulation by recombinant human GH replacement. Clin Endocrinol (Oxf) 52:543–548[CrossRef][Medline]
  39. Johansson JO, Landin K, Tengborn L, Rosen T, Bengtsson BA 1994 High fibrinogen and plasminogen activator inhibitor activity in growth hormone-deficient adults. Arterioscler Thromb 14:434–437[Abstract/Free Full Text]
  40. Sesmilo G, Biller BM, Llevadot J, Hayden D, Hanson G, Rifai N, Klibanski A 2000 Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Ann Intern Med 133:111–122[Abstract/Free Full Text]
  41. Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN 1999 Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab 84:453–457[Abstract/Free Full Text]
  42. Borson-Chazot F, Serusclat A, Kalfallah Y, Ducottet X, Sassolas G, Bernard S, Labrousse F, Pastene J, Sassolas A, Roux Y, Berthezene F 1999 Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 84:1329–1333[Abstract/Free Full Text]
  43. Froesch ER, Guler HP, Schmid C, Zapf J 1990 Therapeutic potential of insulin-like growth factor 1. Trends Endocrinol Metab 1:254–260[Medline]
  44. Brismar K, Fernqvist-Forbes E, Wahren J, Hall K 1994 Effect of insulin on the hepatic production of insulin-like growth factor-binding protein-1 (IGFBP-1), IGFBP-3, and IGF-I in insulin-dependent diabetes. J Clin Endocrinol Metab 79:872–878[Abstract]
  45. Le Roith D, Scavo L, Butler A 2001 What is the role of circulating IGF-I? Trends Endocrinol Metab 12:48–52[CrossRef][Medline]
  46. Conover CA, Lee PD, Kanaley JA, Clarkson JT, Jensen MD 1992 Insulin regulation of insulin-like growth factor binding protein-1 in obese and nonobese humans. J Clin Endocrinol Metab 74:1355–1360[Abstract]



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