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D Scriba, I Aprath-Husmann, WF Blum and H Hauner

OBJECTIVE: Circulating leptin, the product of the ob gene, is known to be closely correlated with adipose tissue mass, but it is also subject to short-term regulation by a variety of hormones including catecholamines. The aim of this study was to investigate the contribution of the three beta-adrenergic receptors to leptin secretion from cultured human adipocytes. DESIGN AND METHODS: The model of in vitro differentiated human subcutaneous adipocytes was used in this study. The presence of the beta-adrenoceptor subtypes was studied by RT-PCR. The functional role of the receptor subtypes was determined by stimulation of lipolysis by selective beta-adrenergic agonists and by measuring glycerol release. Leptin secretion into the medium of cultured human adipocytes from young normal-weight females was measured by radioimmunoassay. RESULTS AND CONCLUSION: In a first set of experiments, the expression of the three beta-adrenergic receptor subtypes in cultured human adipocytes was demonstrated. To test their functional activity, the effect of the beta-adrenoceptor agonists isoproterenol (non-selective agonist), dobutamine (beta(1)-selective), fenoterol (beta(2)-selective) and the beta(3)-selective agonists BRL 37344 and CGP 12177 was studied. All agonists exhibited a dose- and time-dependent stimulation of glycerol release into the medium in a rather uniform manner. Isoproterenol rapidly reduced leptin secretion from cultured subcutaneous adipocytes in a dose-dependent fashion. Incubation with 10(-6)mol/l isoproterenol for 24h resulted in a reduction of the leptin concentration by 48% (P < 0.01). A similar, but less pronounced suppressing effect was seen for dobutamine and fenoterol, whereas both BRL 37344 and CGP 12177 were not effective. These data provide evidence that catecholamines are able to suppress leptin release from differentiated human adipocytes, supporting the concept that leptin secretion is acutely regulated by surrounding hormones. This inhibition is obviously mediated via beta(1)- and beta(2)-adrenergic receptors.

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S Corbetta, P Englaro, S Giambona, L Persani, WF Blum and P Beck-Peccoz

Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur.

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M Schroth, M Groschl, HG Dorr, WF Blum, W Rascher and J Dotsch

OBJECTIVE: In humans, short term changes of serum leptin lead to alterations in food intake and energy expenditure. The objective of the present study was to relate urine leptin concentrations with the extent of proteinuria in patients with nephrotic syndrome (NS). A second goal was to investigate the impact of potential urinary leptin losses on serum leptin concentrations and body composition. DESIGN AND METHODS: Seventeen patients with proteinuria were compared with twenty patients with remission of NS and ten healthy children. Leptin was measured by radioimmunoassay. RESULTS: Urinary leptin excretion in proteinuric patients was significantly higher than in non-proteinuric patients with and without NS and in healthy controls (2.64+/-0.034 microg/g creatinine, 0.026+/-0.05 microg/g creatinine, and 0.073+/-0.11 microg/g creatinine respectively; P<0.001 and P<0.01 respectively compared with controls). Urine leptin positively correlated with urine IgG concentration (P=0.013, r2=0.36) in the proteinuric group. No difference in serum leptin values could be demonstrated between the three groups. CONCLUSIONS: In summary, our data demonstrate a significant leptin excretion in children with severe proteinuria. Proteinuria, however, does not lead to changes in serum leptin, suggesting that the significant loss of leptin is compensated for by sustained up-regulation of leptin production.

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E Schonau, F Westermann, F Rauch, A Stabrey, G Wassmer, E Keller, J Bramswig and WF Blum

OBJECTIVE: To identify parameters which predict individual growth response to recombinant human GH (rhGH) therapy and to combine these parameters in a prediction model. DESIGN: Fifty-eight prepubertal patients with GH deficiency (17 females) participated in this prospective multicenter trial with 1 year of follow-up. METHODS: Auxological measurements, parameters of GH status and markers of bone metabolism were measured at baseline and at 1, 3 and 6 months after the start of rhGH treatment. Correlations with height velocity during the first 12 months of treatment (HV+12) were calculated. Prediction models were derived by multiple regression analysis. RESULTS: The model which best predicted HV+12 combined the following parameters: pretreatment bone age retardation as a fraction of chronological age, pretreatment serum levels of IGF-I, urinary levels of deoxypyridinoline (a marker of bone resorption) after 1 month of treatment and height velocity after 3 months of treatment. This model explained 89% of the variation in HV+12 with a standard deviation of the residuals of 0.93 cm/year. Defining successful rhGH therapy as a doubling of pretreatment height velocity, the model had a specificity of 90% and a sensitivity of 100% in predicting therapeutic success. CONCLUSIONS: This model is an accurate and practicable tool to predict growth response in GH-deficient children. It may help to optimize rhGH therapy by individual dose adjustment and contribute to improved overall outcomes.

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H Gottschling-Zeller, M Birgel, D Scriba, WF Blum and H Hauner

OBJECTIVE: Leptin, the product of the ob gene, is overexpressed in human obesity and increased serum leptin levels are closely correlated with adipose tissue mass, but the regulation of leptin production is not completely understood. The aim of this study was to characterize the role of tumor necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1 in depot-specific secretion of leptin from cultured human adipocytes. DESIGN AND METHODS: We measured the leptin concentrations in the culture medium of omental and subcutaneous abdominal adipocytes taken from severely obese individuals and kept in suspension culture, and studied the effect of TNF-alpha and TGF-beta1 on leptin release. Leptin protein was measured by radioimmunoassay, leptin mRNA was assessed by reverse transcriptase (RT)-PCR relative to a housekeeping gene. RESULTS AND CONCLUSION: Leptin secretion from subcutaneous fat cells was 2- to 3-fold higher than that from omental fat cells after incubation for 2 and 24h respectively. A 2-h exposure of adipocytes to 1nmol/l TNF-alpha and 400pmol/l TGF-beta1 respectively did not significantly affect leptin secretion. Whereas a 24-h incubation with 1nmol/l TNF-alpha also did not influence leptin secretion from fat cells from both depots, exposure of omental fat cells to 400pmol/l TGF-beta1 for 24h resulted in a significant inhibitory effect (by 33%) on leptin secretion (P<0.05). A 24- and 48-h exposure of in vitro differentiated human adipocytes to TNF-alpha led to a significant decrease in leptin mRNA levels to 70 +/- 8% and 49 +/- 13% of controls respectively. Similarly, TGF-beta1 decreased leptin mRNA expression in newly differentiated human adipocytes to 77 +/- 12% after 24h and to 54 +/- 8% after 48h compared with control cultures. These data provide evidence that long-term exposure of human fat cells to TNF-alpha or TGF-beta1 may suppress leptin expression in human adipose tissue. The inhibitory effect of TGF-beta1 appears to be more pronounced in omental as compared with subcutaneous adipocytes.

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M Neuhauser-Berthold, BM Herbert, PM Luhrmann, AA Sultemeier, WF Blum, J Frey and J Hebebrand

OBJECTIVE: The present study investigated the relationship between serum leptin concentrations and resting metabolic rate (RMR) in a large study group of elderly individuals with special consideration of body composition and body fat distribution as possible confounders. DESIGN AND METHODS: The subjects were 122 women (age: 69+/-6 years, body mass index (BMI): 26.3+/-3.6 kg/m(2)) and 82 men (age: 69+/-5 years, BMI: 26.0+/-2.6 kg/m(2)). RMR was measured by indirect calorimetry and body composition by the bioelectrical impedance method. Serum leptin levels were determined by radioimmunoassay. RESULTS: There was a strong correlation between fat mass (FM) and serum leptin levels in both sexes. An age-related decline in leptin levels adjusted for FM was observed only in the women. After adjustment of RMR for both fat-free mass (FFM) and FM, leptin levels were not associated with RMR. In stepwise multiple regression analysis, FFM was the main predictor of RMR, explaining 35.8% and 47.6% of the variance of RMR in men and women respectively. FM did not explain variance in RMR in men, but accounted for 2.6% of the variance in RMR in women. Waist-hip-ratio and age influenced RMR only in males, explaining 5.7% and 4.0% of the variance in RMR respectively. CONCLUSION: Leptin is not a significant predictor of RMR in the elderly, but body composition and distribution of body fat are significantly associated with RMR.

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A Blackburn, RA Dressendorfer, WF Blum, M Erhard, G Brem, CJ Strasburger and E Wolf

To study interactions between insulin-like growth factor-II (IGF-II) and growth hormone (GH) in vivo, we crossed hemizygous transgenic mice carrying phosphoenolpyruvate carboxykinase (PEPCK)-IGF-II fusion genes with hemizygous PEPCK-bovine GH (bGH) transgenic mice. Offspring harbouring both transgenes (IB), the IGF-II transgene (I) or the bGH transgene (B), and non-transgenic littermates (C) were obtained. Blood samples were taken before (end of week 12) and after (end of week 14) the mice had received a diet high in protein and low in carbohydrates to stimulate PEPCK promoter-controlled transgene expression. Mean serum GH concentrations of both B and IB mice corresponded to 900 ng/ml and increased more than twofold (P < 0.001) after 1 week of the high-protein diet. GH concentrations in controls and I mice were less than 20 ng/ml. Serum IGF-II concentrations in I and IB mice were three-to fourfold higher than those in C and B mice. Whereas IGF-II concentrations were not changed by the high-protein diet in the last two groups, serum IGF-II increased significantly in I (P < 0.001) and IB mice (P < 0.05). This increase was significantly (P < 0.05) less pronounced in IB than in C and I mice. Circulating IGF-I concentrations were about twofold (P < 0.001) higher in B and IB than in C and I mice, and showed a tendency to be lower in I than in C and in IB than in B mice when animals were maintained on the standard diet. The high-protein diet did not change circulating IGF-I concentrations in controls and B mice, but resulted in a significant reduction of serum IGF-I concentrations in I (P < 0.05) and IB mice (P < 0.001). Consequently, after PEPCK-IGF-II transgene expression was stimulated, serum IGF-I concentrations were significantly (P < 0.05) lower in I than in C and in IB than in B mice. Serum IGF-binding protein (IGFBP)-2 concentrations were significantly (P < 0.05) higher in I mice than in all other groups when mice were maintained on the standard diet, with a tendency to reduced IGFBP-2 concentrations in B mice. After the high-protein diet, serum IGFBP-2 concentrations did not change in C and I mice, but increased by two- to threefold in B and IB mice (P < 0.001). Serum IGFBP-3 concentrations tended to be greater in B and IB than in C and I mice, but these differences were mostly not significant. IGFBP-4 concentrations were significantly (P < 0.001) increased by GH overproduction in B and IB mice. Our data suggest that the reduction in circulating IGF-I concentrations by increased IGF-II is most probably due to the limited serum IGF binding capacity and the short half-life of free IGFs, rather than to a reduction in GH-dependent IGF-I production. Effects of GH overproduction on serum IGFBP-2 concentrations depend on dietary factors and may be both inhibitory and stimulatory.

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T Seck, P Englaro, WF Blum, C Scheidt-Nave, W Rascher, R Ziegler and J Pfeilschifter

OBJECTIVE: The GH/IGF axis is thought to play an important role in the regulation of body composition throughout life. Changes in body fat stores also affect the activity of the GH/IGF axis, but the mechanisms whereby body fat status is signaled to the GH/IGF axis are poorly understood. The newly discovered protein leptin is exclusively produced by adipocytes, and circulating concentrations of leptin closely reflect body fat stores. DESIGN: We here examined whether leptin might be associated with the activity of the GH/IGF axis in a population-based sample. PATIENTS AND METHODS: Circulating concentrations of leptin, IGF-I, IGF-II, and insulin-like growth factor-binding protein-3 (IGFBP-3) were measured in a population-based sample of 50- to 80-year-old men (n=217) and women (n=198) by specific RIA. RESULTS: All three IGF components were significantly positively correlated with leptin in lean women (body mass index (BMI) <25 kg/m2). IGF-II was also positively correlated with leptin in lean men, and positive correlation of leptin with IGF-I in lean men was of borderline statistical significance. In contrast, no correlation was observed in moderately overweight (BMI 25-30kg/m2) and obese individuals (BMI >30 kg/m2). CONCLUSION: Our study shows that serum leptin concentrations are significantly associated with circulating IGF components in lean elderly subjects. The precise mechanism of this interaction between leptin and the GH/IGF system remains to be determined.

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H Norrelund, CH Gravholt, P Englaro, WF Blum, W Rascher, JS Chistiansen and JO Jorgensen

The regulation of leptin production in humans is poorly understood but appears to depend on total body fat, changes in energy intake and insulin levels. Since growth hormone (GH) is an important regulator of both lipid metabolism and insulin secretion and action, we tested whether GH status directly or indirectly regulates leptin secretion. Circadian serum leptin concentrations were measured in GH-deficient patients in two different protocols involving different modes of acute and prolonged GH exposure. In study I, eight GH-deficient patients all underwent three 4 week study periods in random order: (1) evening (2000 h) s.c. GH injections (2 IU); (2) morning (0800 h) s.c. GH injections (2 IU); (3) no GH administration. At the end of each period the patients were admitted to hospital for 24-h measurements of hormones and metabolites. For comparison, 10 age- and sex-matched healthy untreated subjects were hospitalised under identical conditions. In study II, six GH-deficient patients were hospitalised for 44 h on three occasions, separated by at least 4 weeks without GH treatment. On each occasion they received 2 IU GH, administered i.v. as (1) two boluses (at 2000 and 0200 h), (2) eight boluses (at 3 h intervals starting at 2000 h) or (3) a continuous (2000-2000 h) infusion. In both studies, serum leptin levels peaked between midnight and early morning followed by low day-time levels (P < 0.01). The mode of GH treatment or previous discontinuation did not affect the leptin level (P > 0.05), but the patients had significantly higher leptin levels than the controls (P < 0.01). The diurnal variation in leptin was compared with changes in GH, insulin, non-esterified fatty acids, 3-hydroxybutyrate, insulin-like growth factor I and glucose, but no robust cross-correlations could be demonstrated. The following conclusions were made. (1) The circadian pattern of serum leptin is not influenced by either experimental or spontaneous changes in serum GH concentrations. (2) GH deficiency is associated with elevated leptin levels which most likely reflects increased fat mass in these patients.