Franco Czech Laboratory for Clinical Research on Obesity

Prague, Czech Republic

Franco Czech Laboratory for Clinical Research on Obesity

Prague, Czech Republic

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Pettersson A.M.L.,Karolinska Institutet | Acosta J.R.,Karolinska Institutet | Bjork C.,Karolinska Institutet | Kratzel J.,Karolinska Institutet | And 7 more authors.
Diabetologia | Year: 2015

Aims/hypothesis: Dysregulated expression of metabolic and inflammatory genes is a prominent consequence of obesity causing insulin resistance and type 2 diabetes. Finding causative factors is essential to understanding progression of these pathologies and discovering new therapeutic targets. The transcription factor V-maf musculoaponeurotic fibrosarcoma oncogene homologue B (MAFB) is highly expressed in human white adipose tissue (WAT). However, its role in the regulation of WAT function is elusive. We aimed to characterise MAFB expression and function in human WAT in the context of obesity and insulin resistance. Methods: MAFB mRNA expression was evaluated in human WAT from seven cohorts with large inter-individual variation in BMI and metabolic features. Insulin-induced adipocyte lipogenesis and lipolysis were measured and correlated with MAFB expression. MAFB regulation during adipogenesis and the effects of MAFB suppression in human adipocytes was investigated. MAFB regulation by TNF-α was examined in human primary adipocytes and THP-1 monocytes/macrophages. Results: MAFB expression in human adipocytes is upregulated during adipogenesis, increases with BMI in WAT, correlates with adverse metabolic features and is decreased after weight loss. MAFB downregulation decreases proinflammatory gene expression in adipocytes and interferes with TNF-α effects. Interestingly, MAFB is differentially regulated by TNF-α in adipocytes (suppressed) and THP-1 cells (upregulated). Further, MAFB is primarily expressed in WAT macrophages/monocytes and its expression correlates with macrophage and inflammatory markers. Conclusions/interpretation: Our findings indicate that MAFB is a regulator and a marker of adipose tissue inflammation, a process that subsequently causes insulin resistance. © 2015, Springer-Verlag Berlin Heidelberg.


Siklova-Vitkova M.,Franco Czech Laboratory for Clinical Research on Obesity | Siklova-Vitkova M.,French Institute of Health and Medical Research | Siklova-Vitkova M.,Charles University | Klimcakova E.,Franco Czech Laboratory for Clinical Research on Obesity | And 22 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Context: Obesity is associated with altered plasma levels of adipokines involved in thedevelopment of insulin resistance and obesity-related metabolic disturbances. Objective: The aim was to investigate diet-induced changes in adipokine production in sc abdominal adipose tissue (SAT) during a 6-month, multiphase, weight-reducing dietary intervention. Design, Setting, Participants, and Interventions: Forty-eight obese women followed a dietary intervention consisting of a very low-calorie diet (VLCD) (1 month), followed by a weight-stabilization (WS) period, which consisted of a low-calorie diet (2 months), and a weight-maintenance diet (3 months). Main Outcome Measures: Before and at the end of the VLCD and WS, samples of plasma and SAT were obtained. In a subgroup of 26 women, secretion of adipokines was determined in SAT explants, and in a subgroup of 22 women, SAT mRNA expression was measured. Results: Body weight decreased and insulin sensitivity increased during the intervention. Plasma levels, SAT mRNA expression, and secretion rates of adipocyte-produced adipokines (leptin, serum amyloid A, and haptoglobin) decreased during the VLCD and increased during the WS period. Adipokines produced mainly from stroma-vascular cells (IL-6, IL-8, IL-10, IL-1Ra, TNFα, plasminogen activator inhibitor-1, and monocyte chemoattractant protein-1) increased or remained unchanged during VLCD and decreased to levels equal to or lower than prediet levels during the WS period. The diet-induced changes in homeostasis model assessment of insulin resistance correlated with changes in leptin plasma levels during VLCD, WS, and the entire dietary intervention period. Conclusions: Diet-induced regulation of adipokine production in SAT differs according to their cellular origin (adipocytes vs. stroma-vascular cells) and diet phase (VLCD vs. WS). Insulin-sensitivity changes were associated only with those of plasma leptin. Copyright © 2012 by The Endocrine Society.


Langin D.,French Institute of Health and Medical Research | Langin D.,University Paul Sabatier | Langin D.,Toulouse University Hospital Center | Langin D.,Franco Czech Laboratory for Clinical Research on Obesity
Cell Metabolism | Year: 2011

Adipose tissue is the main site of storage and mobilization of lipid. In a recent study published in Nature, Arner et al. (2011) report that high storage and low removal of adipose triglycerides promotes obesity, whereas low storage and low removal favor the development of dyslipidemia in humans. © 2011 Elsevier Inc.


Rossmeislova L.,Franco Czech Laboratory for Clinical Research on Obesity | Rossmeislova L.,French Institute of Health and Medical Research | Rossmeislova L.,Charles University | Malisova L.,Franco Czech Laboratory for Clinical Research on Obesity | And 29 more authors.
Diabetes | Year: 2013

Calorie restriction-induced weight loss is accompanied by profound changes in adipose tissue characteristics. To determine the effect of weight loss on differentiation of preadipocytes and secretory capacity of in vitro differentiated adipocytes, we established cultures of these cells from paired subcutaneous adipose tissue biopsies obtained before and at the end of weight-reducing dietary intervention (DI) in 23 obese women. Based on lipid accumulation and the expression of differentiation markers, in vitro adipogenesis increased after weight loss and it was accompanied by enhanced expression of genes involved in de novo lipogenesis. This effect of weight loss was not driven by changes of peroxisome proliferator-activated receptor γ sensitivity to rosiglitazone. Weight loss also enhanced the expression of adiponectin and leptin while reducing that of monocyte chemoattractant protein 1 and interleukin-8 by cultured adipocytes. Thus, the weight-reducing (DI) increased adipogenic capacity of preadipocytes and shifted their secretion toward lower inflammatory profile. Reprogramming of preadipocytes could represent an adaptation to weight loss leading to partial restoration of preobese adipose tissue traits and thus contribute to the improvement of metabolic status. However, enhanced adipogenesis could also contribute to the unwanted weight regain after initial weight loss. © 2013 by the American Diabetes Association.


Vila I.K.,French Institute of Health and Medical Research | Vila I.K.,University Paul Sabatier | Badin P.-M.,French Institute of Health and Medical Research | Badin P.-M.,University Paul Sabatier | And 35 more authors.
Cell Reports | Year: 2014

Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4. © 2014 The Authors.


Malisova L.,Charles University | Malisova L.,Franco Czech Laboratory for Clinical Research on Obesity | Malisova L.,French Institute of Health and Medical Research | Kovacova Z.,Charles University | And 14 more authors.
PLoS ONE | Year: 2013

Stress of endoplasmic reticulum (ERS) is one of the molecular triggers of adipocyte dysfunction and chronic low inflammation accompanying obesity. ERS can be alleviated by chemical chaperones from the family of bile acids (BAs). Thus, two BAs currently used to treat cholestasis, ursodeoxycholic and tauroursodeoxycholic acid (UDCA and TUDCA), could potentially lessen adverse metabolic effects of obesity. Nevertheless, BAs effects on human adipose cells are mostly unknown. They could regulate gene expression through pathways different from their chaperone function, namely through activation of farnesoid X receptor (FXR) and TGR5, G-coupled receptor. Therefore, this study aimed to analyze effects of UDCA and TUDCA on human preadipocytes and differentiated adipocytes derived from paired samples of two distinct subcutaneous adipose tissue depots, abdominal and gluteal. While TUDCA did not alter proliferation of cells from either depot, UDCA exerted strong anti-proliferative effect. In differentiated adipocytes, acute exposition to neither TUDCA nor UDCA was able to reduce effect of ERS stressor tunicamycin. However, exposure of cells to UDCA during whole differentiation process decreased expression of ERS markers. At the same time however, UDCA profoundly inhibited adipogenic conversion of cells. UDCA abolished expression of PPARγ and lipogenic enzymes already in the early phases of adipogenesis. This anti-adipogenic effect of UDCA was not dependent on FXR or TGR5 activation, but could be related to ability of UDCA to sustain the activation of ERK1/2 previously linked with PPARγ inactivation. Finally, neither BAs did lower expression of chemokines inducible by TLR4 pathway, when UDCA enhanced their expression in gluteal adipocytes. Therefore while TUDCA has neutral effect on human preadipocytes and adipocytes, the therapeutic use of UDCA different from treating cholestatic diseases should be considered with caution because UDCA alters functions of human adipose cells. © 2013 Mališová et al.


Klimcakova E.,Franco Czech Laboratory for Clinical Research on Obesity | Klimcakova E.,French Institute of Health and Medical Research | Klimcakova E.,Charles University | Roussel B.,French Institute of Health and Medical Research | And 26 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: It is not known whether biological differences reported between sc adipose tissue (SAT) and visceral adipose tissue (VAT) depots underlie the pathogenicity of visceral fat. Objective: We compared SAT and VAT gene expression according to obesity, visceral fat accumulation, insulin resistance, and presence of the metabolic syndrome. Design: Subjects were assigned into four groups (lean, overweight, obese, and obese with metabolic syndrome). Setting: Subjects were recruited at a university hospital. Patients: Thirty-two women were included. Main Outcome Measures: Anthropometric measurements, euglycemic-hyperinsulinemic clamps, blood analyses, and computed tomography scans were performed, and paired samples of SAT and VAT were obtained for DNA microarray-based gene expression profiling. Results: Considering the two fat depots together, 1125 genes were more and 1025 genes were less expressed in lean compared with metabolic syndrome subjects. Functional annotation clustering showed, from lean to metabolic syndrome subjects, progressive down-regulation of metabolic pathways including branched-chain amino acid, fatty acid, carbohydrate, and mitochondrial energy metabolism and up-regulation of immune response genes involved in toll-like receptor, TNF, nuclear factor-κB, and apoptosis pathways. Metabolism and immune response genes showed an opposite correlation with fat mass, fat distribution, or insulin resistance indices. These associations were similar in SAT and VAT, although about 1000 genes showed differential expression between SAT and VAT. Conclusions: The increase in adiposity and the worsening of metabolic status are associated with a coordinated down-regulation of metabolism-related and up-regulation of immune response-related gene expression. Molecular adaptations in SAT prove as discriminating as those in VAT. Copyright © 2011 by The Endocrine Society.


Langin D.,French Institute of Health and Medical Research | Langin D.,Institut Universitaire de France | Langin D.,Toulouse University Hospital Center | Langin D.,Franco Czech Laboratory for Clinical Research on Obesity
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2010

The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a matter of debate, and the molecular mechanisms underlying brown adipocyte development remained largely unknown. In 2009, several studies brought direct evidence for functional brown adipose tissue in adults. New factors involved in brown fat cell differentiation have been identified. Moreover, work on the origin of fat cells took an unexpected path with the recognition of different populations of brown fat cell precursors according to the anatomical location of the fat depots: a precursor common to skeletal muscle cells and brown adipocytes from brown fat depots, and a progenitor cell common to white adipocytes and brown adipocytes that appear in certain conditions in white fat depots. There is also mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications. © 2009 Elsevier B.V. All rights reserved.


PubMed | Franco Czech Laboratory for Clinical Research on Obesity
Type: Journal Article | Journal: International journal of obesity (2005) | Year: 2012

Accumulation of adipose tissue macrophages (ATMs) is observed in obesity and may participate in the development of insulin resistance and obesity-related complications. The aim of our study was to investigate the effect of long-term dietary intervention on ATM content in human adipose tissue.We performed a multi-phase longitudinal study.A total of 27 obese pre-menopausal women (age 39 2 years, body mass index 33.7 0.5 kg m(-2)) underwent a 6-month dietary intervention consisting of two periods: 4 weeks of very low-calorie diet (VLCD) followed by weight stabilization composed of 2 months of low-calorie diet and 3 to 4 months of weight maintenance diet. At baseline and at the end of each dietary period, samples of subcutaneous adipose tissue (SAT) were obtained by needle biopsy and blood samples were drawn. ATMs were determined by flow cytometry using combinations of cell surface markers. Selected cytokine and chemokine plasma levels were measured using enzyme-linked immunosorbent assay. In addition, in a subgroup of 16 subjects, gene expression profiling of macrophage markers in SAT was performed using real-time PCR.Dietary intervention led to a significant decrease in body weight, plasma insulin and C-reactive protein levels. After VLCD, ATM content defined by CD45+/14+/206+ did not change, whereas it decreased at the end of the intervention. This decrease was associated with a downregulation of macrophage marker mRNA levels (CD14, CD163, CD68 and LYVE-1 (lymphatic vessel endothelial hyaluronan receptor-1)) and plasma levels of monocyte-chemoattractant protein-1 (MCP-1) and CXCL5 (chemokine (C-X-C motif) ligand 5). During the whole dietary intervention, the proportion of two ATM subpopulations distinguished by the CD16 marker was not changed.A 6-month weight-reducing dietary intervention, but not VLCD, promotes a decrease in the number of the whole ATM population with no change in the relative distribution of ATM subsets.


PubMed | Franco Czech Laboratory for Clinical Research on Obesity
Type: Clinical Trial | Journal: The Journal of clinical endocrinology and metabolism | Year: 2012

Obesity is associated with altered plasma levels of adipokines involved in the development of insulin resistance and obesity-related metabolic disturbances.The aim was to investigate diet-induced changes in adipokine production in sc abdominal adipose tissue (SAT) during a 6-month, multiphase, weight-reducing dietary intervention.Forty-eight obese women followed a dietary intervention consisting of a very low-calorie diet (VLCD) (1 month), followed by a weight-stabilization (WS) period, which consisted of a low-calorie diet (2 months), and a weight-maintenance diet (3 months).Before and at the end of the VLCD and WS, samples of plasma and SAT were obtained. In a subgroup of 26 women, secretion of adipokines was determined in SAT explants, and in a subgroup of 22 women, SAT mRNA expression was measured.Body weight decreased and insulin sensitivity increased during the intervention. Plasma levels, SAT mRNA expression, and secretion rates of adipocyte-produced adipokines (leptin, serum amyloid A, and haptoglobin) decreased during the VLCD and increased during the WS period. Adipokines produced mainly from stroma-vascular cells (IL-6, IL-8, IL-10, IL-1Ra, TNF, plasminogen activator inhibitor-1, and monocyte chemoattractant protein-1) increased or remained unchanged during VLCD and decreased to levels equal to or lower than prediet levels during the WS period. The diet-induced changes in homeostasis model assessment of insulin resistance correlated with changes in leptin plasma levels during VLCD, WS, and the entire dietary intervention period.Diet-induced regulation of adipokine production in SAT differs according to their cellular origin (adipocytes vs. stroma-vascular cells) and diet phase (VLCD vs. WS). Insulin-sensitivity changes were associated only with those of plasma leptin.

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