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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. Source

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. Source

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. Source

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 21 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. Source

Koc M.,Franco Czech Laboratory for Clinical Research on Obesity | Koc M.,Charles University | Mayerova V.,Franco Czech Laboratory for Clinical Research on Obesity | Mayerova V.,Charles University | And 14 more authors.
Biochemical and Biophysical Research Communications | Year: 2015

Background Adipocytes are cells specialized for storage of neutral lipids. This storage capacity is dependent on lipogenesis and is diminished in obesity. The reason for the decline in lipogenic activity of adipocytes in obesity remains unknown. Recent data show that lipogenesis in liver is regulated by pathways initiated by endoplasmic reticulum stress (ERS). Thus, we aimed at investigating the effect of ERS on lipogenesis in adipose cells. Methods Preadipocytes were isolated from subcutaneous abdominal adipose tissue from obese volunteers and in vitro differentiated into adipocytes. ERS was induced pharmacologically by thapsigargin (TG) or tunicamycin (TM). Activation of Unfolded Protein Response pathway (UPR) was monitored on the level of eIF2α phosphorylation and mRNA expression of downstream targets of UPR sensors. Adipogenic and lipogenic capacity was evaluated by Oil Red O staining, measurement of incorporation of radio-labelled glucose or acetic acid into lipids and mRNA analysis of adipogenic/lipogenic markers. Results Exposition of adipocytes to high doses of TG (100 nM) and TM (1 μg/ml) for 1-24 h enhanced expression of several UPR markers (HSPA5, EDEM1, ATF4, XBP1s) and phosphorylation of eIF2α. This acute ERS substantially inhibited expression of lipogenic genes (DGAT2, FASN, SCD1) and glucose incorporation into lipids. Moreover, chronic exposure of preadipocytes to low dose of TG (2.5 nM) during the early phases of adipogenic conversion of preadipocytes impaired both, lipogenesis and adipogenesis. On the other hand, chronic low ERS had no apparent effect on lipogenesis in mature adipocytes. Conclusions Acute ERS weakened a capacity of mature adipocytes to store lipids and chronic ERS diminished adipogenic potential of preadipocytes. © 2015 Elsevier Inc. All rights reserved. Source

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