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Polak J.,Institute of Clinical and Experimental Medicine | Polak J.,Johns Hopkins University | Polak J.,Charles University | Polak J.,University Hospital of Kralovske Vinohrady | And 8 more authors.
Journal of the American College of Cardiology | Year: 2011

Objectives: Our goal was to examine the role of B-type natriuretic peptide (BNP) in lipolysis regulation in heart failure (HF) patients. Background: Enhanced adipose tissue lipolysis can contribute to myocardial lipid overload, insulin resistance, and cachexia in advanced HF. Natriuretic peptides were recently recognized to stimulate lipolysis in healthy subjects. Methods: Ten nondiabetic HF patients (New York Heart Association functional class III, 50% nonischemic etiology) and 13 healthy subjects (control subjects) of similar age, sex, and body composition underwent a microdialysis study of subcutaneous abdominal adipose tissue. Four microdialysis probes were simultaneously perfused with 0.1 μM BNP132, 10 μM BNP132, 10 μM norepinephrine (NE) or Ringer's solution. Outgoing dialysate glycerol concentration (DGC) was measured as an index of lipolysis. Results: Spontaneous lipolysis was higher in HF patients compared with control subjects (DGC: 189 ± 37 μmol/l vs. 152 ± 35 μmol/l, p < 0.01). Response to NE was similar (p = 0.35) in HF patients and control subjects (DGC increase of 1.7 ± 0.2-fold vs. 1.7 ± 0.4-fold). BNP132 10 μM markedly increased lipolysis in both HF patients and control subjects (DGC increase of 2.8 ± 0.5-fold vs. 3.2 ± 0.3-fold), whereas the response to 0.1 μM BNP132 was more pronounced in HF patients (p = 0.02). In HF patients, spontaneous lipolysis positively correlated with insulin resistance and the response to BNP132 negatively correlated with adiposity. Conclusions: BNP132 exerts strong lipolytic effects in humans. Despite marked elevation of plasma immunoreactive BNP, the responsiveness of adipose tissue to BNP132 is not attenuated in HF, possibly reflecting a deficiency of endogenous bioactive BNP. Lipolytic effects of BNP can contribute to excessive fatty acid mobilization in advanced HF. © 2011 American College of Cardiology Foundation.

Wedellova Z.,Charles University | Wedellova Z.,University Hospital of Kralovske Vinohrady | Kovacova Z.,Charles University | Tencerova M.,Charles University | And 7 more authors.
PLoS ONE | Year: 2013

Contribution of individual adiponectin isoforms to lipolysis regulation remains unknown. We investigated the impact of full-length, trimeric and globular adiponectin isoforms on spontaneous lipolysis in subcutaneous abdominal (SCAAT) and visceral adipose tissues (VAT) of obese and non-obese subjects. Furthermore, we explored the role of AMPK (5'-AMP-activated protein kinase) in adiponectin-dependent lipolysis regulation and expression of adiponectin receptors type 1 and 2 (AdipoR1 and AdipoR2) in SCAAT and VAT. Primary adipocytes isolated from SCAAT and VAT of obese and non-obese women were incubated with 20 μg/ml of: A) full-length adiponectin (physiological mixture of all adiponectin isoforms), B) trimeric adiponectin isoform or C) globular adiponectin isoform. Glycerol released into media was used as a marker of lipolysis. While full-length adiponectin inhibited lipolysis by 22% in non-obese SCAAT, globular isoform inhibited lipolysis by 27% in obese SCAAT. No effect of either isoform was detected in non-obese VAT, however trimeric isoform inhibited lipolysis by 21% in obese VAT (all p<0.05). Trimeric isoform induced Thr172 p-AMPK in differentiated preadipocytes from a non-obese donor, while globular isoform induced Ser79 p-ACC by 32% (p<0.05) and Ser565 p-HSL by 52% (p = 0.08) in differentiated preadipocytes from an obese donor. AdipoR2 expression was 17% and 37% higher than AdipoR1 in SCAAT of obese and non-obese groups and by 23% higher in VAT of obese subjects (all p<0.05). In conclusion, the anti-lipolytic effect of adiponectin isoforms is modified with obesity: while full-length adiponectin exerts anti-lipolytic action in non-obese SCAAT, globular and trimeric isoforms show anti-lipolytic activity in obese SCAAT and VAT, respectively. © 2013 Wedellova et al.

Kovacova Z.,Charles University | Tencerova M.,Charles University | Roussel B.,French Institute of Health and Medical Research | Roussel B.,University Paul Sabatier | And 8 more authors.
International Journal of Obesity | Year: 2011

Objective:Hypoadiponectinemia observed in obesity is associated with insulin resistance, diabetes and atherosclerosis. The aim of the present study was to investigate secretion of adiponectin and its multimeric isoforms by explants derived from subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese and non-obese subjects. Design:Paired samples of SAT and VAT and blood samples were obtained from 23 subjects (10 non-obese and 13 obese) undergoing elective abdominal surgery. Total adiponectin quantities and adiponectin isoforms were measured in conditioned media of explants derived from SAT and VAT using enzyme-linked immunosorbent assay and non-denaturing western blot, respectively. Results:Total adiponectin plasma levels were lower in obese than in non-obese subjects (P<0.05). Secretion of total adiponectin in adipose tissue (AT) explants was lower in obese than in non-obese subjects in SAT (P<0.05) but not in VAT. In both, SAT and VAT, the most abundant isoform released into conditioned media was the high-molecular weight (HMW) form. Its relative proportion in relation to total adiponectin was higher in conditioned media of explants from both fat depots when compared with plasma (P<0.001). The proportion of secreted HMW vs total adiponectin was higher in VAT than in SAT explants in the group of non-obese individuals (49.3±3.1% in VAT vs 40.6±2.8% in SAT; P<0.01), whereas no difference between the two depots was found in obese subjects (46.2±3.0 % in VAT vs 46.0±2.4 % in SAT). Conclusion:Obesity is associated with the decrease of total adiponectin secretion in SAT. The profile of adiponectin isoforms secreted by SAT and VAT explants differs from that in plasma. Secretion of total adiponectin and HMW isoform of adiponectin are different in obese and non-obese subjects in relation to AT depot.International Journal of Obesity advance online publication, 6 December 2011; doi:10.1038/ijo.2011.223.

Wedellova Z.,Charles University | Wedellova Z.,University Hospital of Kralovske Vinohrady | Dietrich J.,Wildau University of Applied Sciences | Siklova-Vitkova M.,Charles University | And 9 more authors.
Physiological Research | Year: 2011

Adiponectin is an adipokine increasing glucose and fatty acid metabolism and improving insulin sensitivity. The aim of this study was to investigate the role of adiponectin in the regulation of adipocyte lipolysis. Human adipocytes isolated from biopsies obtained during surgical operations from 16 non-obese and 17 obese subjects were incubated with 1) human adiponectin (20 μg/ml) or 2) 0.5 mM AICAR - activator of AMPK (adenosine monophosphate activated protein kinase). Following these incubations, isoprenaline was added (10-6 M) to investigate the influence of adiponectin and AICAR on catecholamine-induced lipolysis. Glycerol concentration was measured as lipolysis marker. We observed that adiponectin suppressed spontaneous lipolysis by 21 % and isoprenaline-induced lipolysis by 14 % in non-obese subjects. These effects were not detectable in obese individuals, but statistically significant differences in the effect of adiponectin between obese and non-obese were not revealed by two way ANOVA test. The inhibitory effect of AICAR and adiponectin on lipolysis was reversed by Compound C. Our results suggest, that adiponectin in physiological concentrations inhibits spontaneous as well as catecholamine-induced lipolysis. This effect might be lower in obese individuals and this regulation seems to involve AMPK. © 2011 Institute of Physiology v.v.i., Academy of Sciences of the Czech Republic.

Kostka R.,University Hospital of Kralovske Vinohrady | Gurlich R.,University Hospital of Kralovske Vinohrady | Koldova L.,University Hospital of Kralovske Vinohrady
Acta Chirurgica Belgica | Year: 2012

Background : Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal (GI) tract. They are believed to originate from the interstitial cells of Cajal (ICCs) or from the pre cursors of ICCs. Most GISTs show an activating mutation in either the c-kit or platelet-derived growth factor receptor alpha (PDGFRA) gene. Tumor size, mitotic rate, and anatomic location correlate with potential malignancy and recurrence rate. Patients and methods :A total of 12 patients were diagnosed to have GIST based on histology or immunohistochemistry of a biopsy or resection specimen obtained from the GI tract in the 2004-2009 period. The material was obtained using retrospective data collection. Results : The male to female ratio was 1:1 ; mean age 68.2 ± 7.0 years. The stomach was involved in seven cases (58.3%), the small intestine in four (33.3%), and from a lymph node without the finding of a primary tumor was material obtained in one case (8.3%). The course was asymptomatic in four patients (incidental findings). All 12 patients had surgery ; a curative procedure was undertaken in 11 patients. A spindle-cell pattern was present in 8/12 of the specimens examined, epithelioid in 2/12 and a mixed pattern in two cases. Ten specimens were CD117 positive (83.3%), two were negative ; all 10 examined specimens exhibited CD34 positivity while two were not examined. The findings were classified as GISTs with a high risk of progressive disease in three patients, with a moderate risk in one patient, and a low or very low degree of malignancy in five patients. GISTs smaller than 2 cm in three patients were regarded as essentially benign. All patients with low and very low risk of progressive disease survive for 1 to 5 years free of signs. Of the three patients with high degree of malignancy, one died within one year for dissemination, the two remaining patients survive for over two years and six month postoperatively on therapy with tyrosine kinase inhibitors. Conclusion : Tumors classified as GISTs with low and very low risk of progression are associated with a very good prognosis, with virtually all patients surviving 5 years. In patients with high risk or progressive diseases, the prognosis of 5-year survival is much poorer. The main therapeutic option is surgical removal of the tumor (resection or broad excision). Agents showing promise for patients with malignant forms of GISTs are tyrosine kinase receptor inhibitors. Although imatinib is currently used as a first line treatment for all patients with metastatic or unresectable GISTs, it is likely that this treatment will change in the future based on the underlying mutational status.

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