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Elisabeth Hjøllund, Bjørn Richelsen, and Oluf Pedersen

Abstract. We have described the receptor binding of A 14-labelled [125I]insulin to viable adipocytes, hepatocytes, monocytes and erythrocytes from the pig. For all cell types the binding was of high affinity, specific for insulin, the non-specific binding low and degradation of insulin in the medium was minimal. At 24°C, steady state insulin binding was achieved in all four cell types. At 37°C, steady state insulin binding could be measured to adipocytes and hepatocytes. Specific insulin binding levels and receptor affinity for blood and fat cells from the pig are comparable to that in human cells, whereas differences, especially according to affinity, exist between pig and rat cell insulin receptor binding. It is therefore concluded that the pig is a more suitable model for studies of insulin binding in man than rodents. Finally, no correlations between the individual binding levels to the different cell types were observed. Hence, measurement of insulin binding to the easier available blood cells cannot replace studies of insulin binding to target cells of insulin.

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Steen B Pedersen, Jens D Børglum, Kim Brixen, and Bjørn Richelsen

Pedersen SB, Borglum JD, Brixen K, Richelsen B. Relationship between sex hormones, body composition and metabolic risk parameters in premenopausal women. Eur J Endocrinol 1995;133: 200–6. ISSN 0804–4643

The metabolic complications associated with obesity are dependent upon the degree of obesity and the distribution of adipose tissue. In order to evaluate the associations between sex hormone status, metabolic risk parameters, obesity and distribution of adipose tissue, 25 premenopausal women with a wide range of body mass index (19.3–48.1 kg/m2 were studied. Body composition was determined by dual-energy x-ray absorptiometry scan and anthropometric measurements; in addition, lipid and sex hormone status were determined and an oral glucose tolerance test was performed. We found that sex hormone-binding globulin was correlated negatively with total fat mass (r = –0.77, p < 0.001) and especially with abdominal localization of adipose tissue (r = –0.85, p < 0.001). Free testosterone was correlated positively with total fat mass (r = 0.40, p < 0.05) and with abdominal fat accumulation (r = 0.64, p < 0.001). Free estrogen was correlated negatively with total amount of adipose tissue (r = –0.40, p < 0.05) but not with the distribution of adipose tissue, Finally, total fatness, abdominal localization of adipose tissue and free testosterone were all associated with elevated metabolic risk factors. However, multiple regression analysis revealed that only abdominal localization of adipose tissue was independently associated with a higher risk profile, whereas the effects of sex hormones or total fatness disappeared when abdominal localization of adipose tissue was included in the analysis. In conclusion, these findings in premenopausal women indicate that the connection between sex hormones and metabolic risk factors might be indirect, probably operating through alterations in the amount of adipose tissue in the abdominal region.

SB Pedersen, University Clinic of Endocrinology and Internal Medicine, Aarthus, Amtssygehus, Tage Hansensgade, DK-8000 Aarhus C, Denmark

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Jens M Bruun, Bente Stallknecht, Jørn W Helge, and Bjørn Richelsen

Objective: Interleukin (IL)-18 is associated with obesity, insulin resistance, and cardiovascular disease. The present study compared 1) IL-18 in adipocytes versus stromal vascular (SV) cells, 2) IL-18 in plasma and adipose tissue (AT) in obese versus lean subjects, and 3) IL-18 in plasma, AT, and skeletal muscle (SM) in obese subjects after weight loss.

Subjects and methods: At baseline, plasma and AT IL-18 in 23 obese subjects were compared with that in 12 lean subjects. The obese subjects were submitted to a 15-week life-style intervention (hypocaloric diet and daily exercise) after which plasma samples, AT, and SM biopsies were obtained. Analyses were performed by ELISA and RT-PCR respectively.

Results: IL-18 expression in isolated adipocytes was ~2% of that in SV cells. Plasma IL-18 was higher in obese subjects (P < 0.001) and associated with insulin resistance (HOMA; P < 0.001). AT expression of IL-18, CD14, and CD68 was higher in obese (P < 0.01). The intervention reduced body weight (P < 0.001), plasma IL-18 (P < 0.001), and increased insulin sensitivity (HOMA; P < 0.05). AT and SM expression of IL-18 remained unchanged after the intervention. Changes in plasma IL-18 were associated with changes in insulin sensitivity (P < 0.05) but not with BMI or AT expression of IL-18.

Conclusion: Plasma IL-18 is associated with changes in insulin resistance and reduced after weight loss. AT expression of IL-18 is increased in obesity but not affected by weight loss, indicating that changes in plasma IL-18 are related to insulin resistance rather than changes in obesity per se.

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Oluf Pedersen, Bjørn Richelsen, Jens Bak, Jon Arnfred, Jørgen Weeke, and Ole Schmitz

Abstract. Insulin action on glucose utilization was characterized in adipocytes from 10 thyrotoxic patients, 6 hypothyroid patients and 10 age- and sex-matched control subjects. In thyrotoxic patients insulin binding at low insulin concentrations was reduced (P < 0.05) and accompanied by impaired insulin sensitivity of glucose transport (P < 0.02), glucose oxidation (P < 0.05) and lipogenesis (P < 0.05). Glucose transport and glucose oxidation rates also exhibited depressed maximal insulin responsiveness (P < 0.05). In hypothyroid patients insulin binding was reduced, too, (P < 0.05) and associated with impaired sensitivity to insulin of glucose transport (P < 0.05). Both glucose transport and lipogenesis rates showed decreased maximal insulin responsiveness (P < 0.05). In conclusion: In man, both hyper- and hypothyroidism are characterized by insulin resistance of adipocyte glucose utilization localized to insulin binding as well as to insulin-stimulated glucose transport and metabolism.

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Per H Andersen, Bjørn Richelsen, Jens Bak, Ole Schmitz, Niels S Sørensen, Rodolphe Lavielle, and Oluf Pedersen

In a short-term (eight days) double-blind crossover study involving 10 obese patients, the effects of dexfenfluramine on glucose and lipid metabolism were examined. The protocol comprised whole body in vivo measurements (hyperinsulinemic euglycemic clamp in combination with indirect calorimetry) and in vitro studies of isolated adipocytes (lipolysis and glucose transport). All study participants were weight stable during the study period (103.1±3.2, placebo vs 103.3±3.1 kg, dexfenfluramine, NS). The following parameters were significantly reduced after dexfenfluramine treatment: fasting levels of plasma glucose (6.2±0.2 vs 5.7±0.2 mmol/l, p<0.01), serum insulin (168.0±14.5 vs 138.9±7.9 pmol/l, p<0.05), serum C-peptide (0.68±0.03 vs 0.58±0.02 nmol/l, p<0.05) and total serum cholesterol (6.07±0.41 vs 5.48±0.38 mmol/l, p< 0.01). In the basal state glucose oxidation rate was significantly reduced by 36% (p<0.001), whereas non-oxidative glucose disposal was significantly increased by 41% (p<0.01), following dexfenfluramine treatment. Insulin-stimulated (2 mU·kg−1·min−1) glucose disposal rate tended to be increased (18%, p=0.10) after dexfenfluramine. In conclusion, dexfenfluramine possesses beneficial regulatory effects on glucose and lipid metabolism in non-diabetic obese patients, independently of weight loss.

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Ulrick Espelund, Jens Meldgaard Bruun, Bjørn Richelsen, Allan Flyvbjerg, and Jan Frystyk

Background: In normal subjects up to 10% of circulating insulin-like growth factor II (IGF-II) consists of pro-IGF-II. However, its regulation and biological impact remains unknown. In obese subjects, serum free and total IGF-II are increased, and we therefore investigated the impact of obesity and diet on serum pro-IGF-II.

Design: Non-diabetic, obese subjects (n = 34) with a body mass index (BMI) of 38.9 ± 0.5 kg/m2 were subjected to 8 weeks with very low calorie diet (800 kcal/day) followed by 12 weeks with a weight-stabilizing diet. Fasting serum was collected before the study, and after 8 and 20 weeks. Pro-IGF-II was determined after acid-gel chromatography using a novel, highly specific in-house assay, free and total IGFs were measured after ultrafiltration and acid-ethanol extraction, respectively, and IGF-binding proteins (IGFBPs) were measured with specific immunoassays.

Results: Diet reduced BMI and fasting levels of insulin and glucose (P < 0.001). Serum pro-IGF-II was markedly reduced in obese subjects as compared with matched normal-weight controls (means and 95% confidence intervals: 93 μg/l (82–104 μg/l) versus 171 μg/l (152–192 μg/l), respectively; P < 0.001), and levels remained unchanged after the weight loss. In contrast, during the study period total and free IGF-II decreased (P < 0.05), whereas total IGF-I, IGFBP-1 and IGFBP-2 increased (P < 0.001). Serum free IGF-I remained unaltered. Cross-sectional and longitudinal correlation analyses showed that pro-IGF-II was closer and more consistently associated with IGF-I than IGF-II.

Conclusion: This study demonstrates that pro-IGF-II is reduced in obesity, in contrast to mature IGF-II. This indicates a hitherto unrecognized link between nutrition and pro-IGF-II. In addition, our data indicate that pro-IGF-II is regulated independently of mature IGF-II.

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Tore Christiansen, Søren K Paulsen, Jens M Bruun, Kristian Overgaard, Steffen Ringgaard, Steen B Pedersen, Vincenzo Positano, and Bjørn Richelsen

Objective

Weight loss with preferential effect on the visceral adipose tissue (VAT) depot could have important clinical benefits. In this study, we investigated the independent and combined effect of regular exercise and diet induced weight loss on body fat distribution.

Design

Randomized control design of i) exercise-only (EXO; 12 weeks of exercise without diet-restriction), ii) hypocaloric-diet (DIO; 8 weeks of very low energy diet (VLED 600 kcal/day) followed by 4-weeks weight maintenance diet) and iii) hypocaloric-diet and exercise (DEX; 8 weeks VLED 800 kcal/day+a 4-week weight maintenance diet combined with exercise throughout the 12 weeks).

Subjects

Seventy-nine obese males and females were included.

Measurements

Body fat distribution was quantified by magnetic resonance imaging (MRI)-technology.

Results

In the EXO group, the weight loss (3.5 kg) and the relative reduction in VAT (18%) was significantly lower compared with the weight losses in the DIO and DEX groups (12.3 kg; P<0.01) and to the reduction in VAT (30–37%; P<0.01). In all the three groups, the relative reduction of VAT was higher as compared with the reduction in fat mass (FM; combining all fat depots determined by MRI; P<0.01 for all comparisons). The changes in VAT were associated with changes in FM and related to the initial VAT/FM ratio (r 2=0.72; P<0.01).

Conclusion

Exercise has no additional effects in reduction of the VAT depot, compared with the major effects of hypocaloric diet alone. In addition, the effects of exercise per se on VAT are relatively limited. The effects on the VAT depot are closely associated with changes in total FM.

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Erik L Madsen, Aila Rissanen, Jens M Bruun, Kristin Skogstrand, Serena Tonstad, David M Hougaard, and Bjørn Richelsen

Objective

To investigate the effects of: I) short- (8 weeks), II) long-term (3 years) weight loss, and III) the degree of weight loss on circulating levels of adiponectin, high sensitive-C reactive protein (hs-CRP), and fibrinogen in obese subjects. Moreover, to evaluate the effect of the lipase inhibitor, orlistat, on these parameters.

Design

Weight loss induced in 93 obese subjects (mean weight: 108.9±15.8 kg) through 8-week very-low-energy diet (VLED, 800 kcal/day) followed by randomization to orlistat or placebo together with lifestyle intervention for further 3 years. Adiponectin and hs-CRP were measured at baseline, after 8 weeks of VLED and 6, 12, and 36 months after the VLED by flowmetric xMAP technology (Luminex Multi-Analyte Profiling System, Luminex Corp., Austin, TX, USA). Fibrinogen was measured in a coagulation assay.

Results

Weight loss after VLED treatment was 14.3±4.5 kg and after 3 years 7.7±8.7 kg. Orlistat-treated subjects regained 3.9 kg less than placebo-treated from the end of the VLED to 3 years (P=0.01). No differences were detected between the two groups regarding changes in adiponectin, hs-CRP, or fibrinogen. Accordingly, the groups were combined for further analyses. Serum adiponectin increased by 22% (P<0.05) after the VLED but returned to baseline after 3 years. Both short- and long-term weight losses needed to be in excess of 10% (∼12 kg) in order to increase adiponectin levels significantly. Weight loss was associated with a significant decrease in hs-CRP. Fibrinogen decreased by 12% (P<0.05) after 3 years.

Conclusions

In obese subjects, weight loss was associated with an increase in serum adiponectin and a decrease in hs-CRP and plasma fibrinogen. Long-term weight loss (3 years) must exceed 10% to induce a combined significant improvement in these inflammatory markers.

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Jens OL Jørgensen, Sten B Pedersen, Jens Børglum, Jan Frystyk, Ken KY Ho, Jens S Christiansen, Hans Ørskov, Werner F Blum, and Bjørn Richelsen

Jørgensen JOL, Pedersen SB, Borglum J, Frystyk J, Ho KKY, Christiansen JS, Ørskov H, Blum WF, Richelsen B. Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study. Eur J Endocrinol 1995;133:65–70. ISSN 0804–4643

Obesity is associated with suppressed growth hormone (GH) concentrations but relatively little is known about insulin-like growth factors(IGFs) and binding proteins for GH and IGFs (GHBP and IGFBPs) and the modulatory effect of GH administration. In a double-blind, crossover design we studied the impact of 5 weeks of placebo or GH administration (0.03 mg·kg−1 body wt·day−1) in nine obese women (mean± sem; age 30.4 ± 2.4 years; body mass index 37.0 ± 2.8kg/m2) on IGF-I, IGF-II, IGFBP-1 and -3 and GHBP. Serum IGF-I (μg/l) levels were subnormal and increased significantly following GH (117 ± 16 (placebo) vs 434 ± 33 (GH) vs 198 ± 15 (control (p < 0.01)). By contrast, serum IGF-II (μg/l) levels were in the normal range and remained unchanged (608 ± 20 (placebo) vs 647 ± 40 (GH) (NS)). Serum IGFBP-3 was in the normal range and increased significantly during GH treatment, although relatively less than IGF-I, such that the molar ratio between IGF-I and IGFBP-3 increased with GH treatment, whereas the ratio between IGF-I + IGF-II and IGFBP-3 remained unchanged. Serum IGFBP-1 was low in the placebo situation but became further and almost completely suppressed during GH treatment. During a 2-h hyperinsulinemic, euglycemic glucose clamp, IGFBP-1 decreased in the placebo study and remained suppressed during GH. Serum GHBP (nmol/l) levels were elevated substantially compared to non-obese controls (p < 0.001) and did not change during GH treatment (2.37 ± 0.36 (placebo) vs 2.21 ± 0.25 (GH) vs 0.80 ± 0.19 (control)). In conclusion. obese subjects have low total IGF-I levels but may exhibit relatively increased free IGF-I levels due to the suppression of IGFBP-1. This presumed elevation in free IGF-1 in obesity may explain the normal levels of IGFBP-3 and IGF-II, which contrasts with classic GH deficiency. Furthermore, obese subjects are responsive to exogenous GH in terms of total IGF-I generation and normalization of the ratio between IGF-I and IGFBP-3. Finally, obesity is associated with marked elevations in GHBP levels that were unaffected by 5 weeks of GH administration.

Jens OL Jørgensen, Medical Department M, Aarhus Kommunehospital, DK-8000 C, Aarhus, Denmark

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Peter Breining, Steen B Pedersen, Mads Kjolby, Jacob B Hansen, Niels Jessen, and Bjørn Richelsen

Objective

Activation of brown adipose tissue is a promising strategy to treat and prevent obesity and obesity-related disorders. Activation of uncoupling protein 1 (UCP1) leads to uncoupled respiration and dissipation of stored energy as heat. Induction of UCP1-rich adipocytes in white adipose tissue, a process known as ‘browning’, serves as an alternative strategy to increase whole body uncoupling capacity. Here, we aim to assess the association between parathyroid hormone (PTH) receptor expression and UCP1 expression in human adipose tissues and to study PTH effects on human white and brown adipocyte lipolysis and UCP1 expression.

Design

A descriptive study of human neck adipose tissue biopsies substantiated by an interventional study on human neck-derived adipose tissue cell models.

Methods

Thermogenic markers and PTH receptor gene expression are assessed in human neck adipose tissue biopsies and are related to individual health records. PTH-initiated lipolysis and thermogenic gene induction are assessed in cultured human white and brown adipocyte cell models. PTH receptor involvement is investigated by PTH receptor silencing.

Results

PTH receptor gene expression correlates with UCP1 gene expression in the deep-neck adipose tissue in humans. In cell models, PTH receptor stimulation increases lipolysis and stimulates gene transcription of multiple thermogenic markers. Silencing of the PTH receptor attenuates the effects of PTH indicating a direct PTH effect via this receptor.

Conclusion

PTH 1 receptor stimulation by PTH may play a role in human adipose tissue metabolism by affecting lipolysis and thermogenic capacity.