Papers by Isabelle Dugail
Journal of Lipid Research, 1992
We have investigated the molecular mechanism of the overactivity of fatty acid synthetase (FAS) i... more We have investigated the molecular mechanism of the overactivity of fatty acid synthetase (FAS) in adipose tissue from the genetically obese Zucker rat. Purified FAS from lean and obese rat adipose tissues displayed kinetics constants, molecular weight, and immunological properties that were identical. Western blot analysis revealed that FAS overactivity in obese versus lean rat adipose tissue was paralleled by a proportionate increase in FAS mass, Le., 4-fold increase in suckling normoinsulinemic 16-day-old pups and 25-fold in weaned hyperinsulinemic 30-day-old rats. The determination of absolute FAS mass disclosed that FAS was quantitatively a major protein in obese rat adipose tissue accounting for 13% of cytosolic proteins versus 2% in lean rat at 30 days of age. FAS hyperabundance could be ascribed to an increased relative rate of FAS synthesis that was 6-fold higher in obese than in lean rat adipose tissue. Northern blot analysis demonstrated that FAS mRNA levels in obese rats were increased 4-and 14-fold over those of lean rats at 16 and 30 days of age, respectively, in very close proportion to the 3-and 15-fold increases in FAS gene transcription rates revealed by nuclear run-on assays. Southern analysis of genomic DNA did not allow for detecting amplification or any major structural changes in the FAS gene. e It is concluded that FAS overactivity, shown here to be a lifelong and general feature of all adipose tissue sites in the obese rat, arises primarily from FAS gene overtranscription.-Guichard, C., I. Dugail, X. Le Liepvre, and M. Lavau. Genetic regulation of fatty acid synthetase expression in adipose tissue: overtranscription of the gene in genetically obese rats.
Autophagy, 2020
Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to interven... more Adipose tissue (AT) fibrosis in obesity compromises adipocyte functions and responses to intervention induced-weight loss. It is driven by AT progenitors with dual fibro/adipogenic potential, but pro-fibrogenic pathways activated in obesity remain to be deciphered. To investigate the role of macroautophagy/autophagy in AT fibrogenesis, we used Pdgfra-Cre Ert2 transgenic mice to create conditional deletion of Atg7 alleles in AT progenitor cells (Atg7 cKO) and examined sex-dependent, depotspecific AT remodeling in high-fat diet (HFD)-fed mice. Atg7 cKO mice had markedly decreased extracellular matrix (ECM) gene expression in visceral, subcutaneous and epicardial adipose depots compared to Atg7 lox/lox littermates. ECM gene program regulation by autophagy inhibition occurred independently of changes in the mass of fat tissues or adipocyte numbers of specific depots, and could be mimicked in cultured preadipocytes treated with pharmacological or siRNA-mediated autophagy disruptors. We found that autophagy inhibition promotes global cell-autonomous remodeling of the paracrine TGF-BMP family landscape, whereas ECM gene modulation was independent of the autophagic regulation of GTF2IRD1. The progenitor-specific mouse model of Atg7 inhibition confirms requirement of autophagy for white/beige adipocyte turnover, and combined to in vitro experiments, reveal progenitor autophagy dependence for AT fibrogenic response to HFD, through paracrine remodeling of TGF-BMP factors balance.
Biochimie, 2017
Phosphatidylglycerols (PGs) are specific phospholipids bearing negatively charged polar headgroup... more Phosphatidylglycerols (PGs) are specific phospholipids bearing negatively charged polar headgroups. Although recognized for long as a major lipid component of membranes in bacteria, it is considered a minor lipid in higher eukaryotes, due to its low abundance in biological fluids or tissues. However, new sensitive lipidomic approaches now provide tools for accurate quantification of PGs in biological samples, and this is likely to uncover new roles for these phospholipids in the near future. This paper reviews our present knowledge in PG function, from studies in microbes and eukaryotic cells, and gathers in one place a diverse range of information spread across many fields. The physical properties of PGs, their biological distribution and molecular functions make them potential actors in host-microbe interaction.
Proceedings of the National Academy of Sciences of the United States of America, Jan 31, 2017
The abundance of epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), the... more The abundance of epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), the most frequent cardiac arrhythmia. However, both the origin and the factors involved in EAT expansion are unknown. Here, we found that adult human atrial epicardial cells were highly adipogenic through an epithelial-mesenchymal transition both in vitro and in vivo. In a genetic lineage tracing the WT1(CreERT2+/-)Rosa(tdT+/-) mouse model subjected to a high-fat diet, adipocytes of atrial EAT derived from a subset of epicardial progenitors. Atrial myocardium secretome induces the adipogenic differentiation of adult mesenchymal epicardium-derived cells by modulating the balance between mesenchymal Wingless-type Mouse Mammary Tumor Virus integration site family, member 10B (Wnt10b)/β-catenin and adipogenic ERK/MAPK signaling pathways. The adipogenic property of the atrial secretome was enhanced in AF patients. The atrial natriuretic peptide secreted by atrial myocytes is a major adipogenic f...
Autophagy, 2015
In the context of elevated prevalence of obesity-associated metabolic diseases in the human popul... more In the context of elevated prevalence of obesity-associated metabolic diseases in the human population wordwide, interest in the autophagy degradation pathway is increasing, due to close links with energy metabolism, nutritional state, and inflammation. Here we highlight recent data focusing on adipose tissue which demonstrate alterations in fat cell autophagic flux in human obesity.
Biochemical Journal, 1989
Adipsin gene expression as assessed by mRNA amounts was examined in adipose tissue of genetically... more Adipsin gene expression as assessed by mRNA amounts was examined in adipose tissue of genetically obese rats at the onset (16 days of age) or at later stages (30 and 60 days of age) of obesity. Amounts of mRNA were equivalent in obese and lean rats at 16 days of age. In adult rats, we observed a 2-fold decrease in adipsin mRNA in the obese rats compared with control lean rats, which was abolished by weaning the animals on a high-fat diet. Our data show that, in sharp contrast with genetically obese mice, adipsin mRNA is not suppressed in genetically obese Zucker rats.
Diabetes, 2014
Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell ... more Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell types. Loss of caveolae produces lipodystrophic diabetes in humans, which cannot be reversed by endothelial rescue of caveolin expression in mice, indicating major importance of adipocyte caveolae. However, how caveolae participate in fat cell functions is poorly understood. We investigated dynamic conditions of lipid store fluctuations and demonstrate reciprocal regulation of caveolae density and fat cell lipid droplet storage. We identified caveolin-1 expression as a crucial step in adipose cell lines and in mice to raise the density of caveolae, to increase adipocyte ability to accommodate larger lipid droplets, and to promote cell expansion by increased glucose utilization. In human subjects enrolled in a trial of 8 weeks of overfeeding to promote fattening, adipocyte expansion response correlated with initial caveolin-1 expression. Conversely, lipid mobilization in cultured adipocyt...
Médecine sciences : M/S, 2007
Reproduction Nutrition Développement, 1985
Journal of Hepatology, 2015
We thank Assistance Publique-Hôpitaux de Paris (APHP) and the Direction of Clinical Research, the... more We thank Assistance Publique-Hôpitaux de Paris (APHP) and the Direction of Clinical Research, the Programme Hospitalier de Recherche Clinique for supporting clinical investigations (AOR 02076 to K.C.). This work was also supported by the European Commission (Collaborative Project FP6 ''Hepatic and adipose tissue and functions in the metabolic syndrome'' HEPADIP, see http://www.hepadip.org/, contract LSHM-CT-2005-018734). The research leading to these results received funding from the European Union Seventh Framework Program (FP7/2007-2013) under grant agreement no. Health-F2-2009-241762, for the FLIP project. We thank the Société Française de Nutrition (SFN) for financial support (JAW). Authors' contributions: KA performed the experiments and data analysis, drafted the manuscript, and prepared figures. ML performed LC-MS/MS analysis, NS performed machine learning analysis and prepared figures. CP, JAW and JLB provided clinical samples, PL and AK participated in study design and manuscript editing. KC, ID and JT conceived the study, participated in its design, coordination, and data analysis, and helped write and edit the manuscript.
Endocrinology, 2015
During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistan... more During obesity, a hypoxic state develops within the adipose tissue, resulting in insulin resistance. To understand the underlying mechanism, we analyzed the involvement of caveolae because they play a crucial role in the activation of insulin receptors. In the present study, we demonstrate that in 3T3-L1 adipocytes, hypoxia induces the disappearance of caveolae and inhibits the expression of Cavin-1 and Cavin-2, two proteins necessary for the formation of caveolae. In mice, hypoxia induced by the ligature of the spermatic artery results in the decrease of cavin-1 and cavin-2 expression in the epididymal adipose tissue. Down-regulation of the expression of cavins in response to hypoxia is dependent on hypoxia-inducible factor-1. Indeed, the inhibition of hypoxia-inducible factor-1 restores the expression of cavins and caveolae formation. Expression of cavins regulates insulin signaling because the silencing of cavin-1 and cavin-2 impairs insulin signaling pathway. In human, cavin-1 a...
Progress in Lipid Research, 2009
Journal of Hepatology, 2011
Background & Aims: The adiponutrin/PNPLA3 (patatin-like phospholipase domain-containing protein 3... more Background & Aims: The adiponutrin/PNPLA3 (patatin-like phospholipase domain-containing protein 3) variant I148M has recently emerged as an important marker of human fatty liver disease. In order to understand the role of the adiponutrin/ PNPLA3 protein, we investigated the regulation of its expression in both human and mouse hepatocytes. Methods: Adiponutrin/PNPLA3 and lipogenic enzyme expression was determined by real-time PCR analysis in a wide panel of analysis in vivo in the mouse liver and in vitro in murine hepatocytes and human hepatocyte cell lines infected with ChREBP or SREBP1c-expressing adenoviruses. Results: We show that in the mouse liver, adiponutrin/PNPLA3 gene expression is under the direct transcriptional control of ChREBP (carbohydrate-response element-binding protein) and SREBP1c (sterol regulatory element binding protein1c) in response to glucose and insulin, respectively. In silico analysis revealed the presence of a ChoRE (carbohydrate response element) and of a SRE (sterol response element) binding site on the mouse adiponutrin/PNPLA3 gene promoter. Point mutation analysis in reporter gene assays identified the functional response of these two binding sites in the mouse adiponutrin/ PNPLA3 promoter. In contrast, in human immortalized hepatocytes and in HepG2 hepatoma cells, only SREBP1c was able to induce adiponutrin/PNPLA3 expression, whereas ChREBP was unable to modulate its expression. Conclusions: All together, our results suggest that adiponutrin/ PNPLA3 is regulated by two key factors of the glycolytic and lipogenic pathways, raising the question of its implication in the metabolism of carbohydrates and lipids.
Journal of Biological Chemistry, 1996
We have previously shown that the proximal 2-kb sequence of the fatty acid synthase (FAS) promote... more We have previously shown that the proximal 2-kb sequence of the fatty acid synthase (FAS) promoter transfected into rat adipocytes was highly sensitive to the cellular context, displaying an overactivity in obese (fa/ fa) versus lean Zucker rat adipocytes. Using deletional analysis, we show here that FAS promoter activity mainly depends on a region from ؊200 to ؊126. This sequence exerts a strong negative effect on FAS promoter in adipocytes from lean rats but not in those from obese rats, resulting in a marked overtranscriptional activity in the latter cells. This region, fused to a heterologous promoter, the E1b TATA box, induced differential levels of gene reporter activity in lean and obese rat adipocytes, indicating it harbors fa-responsive element(s). Whatever the rat genotype, adipocyte nuclear proteins were shown to footprint the same protected sequence within the fa-responsive region, and supershift analysis demonstrated that Sp1 or Sp1-like proteins were bound to this DNA subregion. Compelling evidence that the Sp1 binding site contained in this sequence was implicated in the differential promoter activity in lean versus obese rats, was provided by the observation that mutations at this Sp1 site induced a 2.5-fold increase in FAS promoter activity in adipocytes from lean rats, whereas they had no effect in adipocytes from obese rats.
Journal of Biological Chemistry, 2005
Scavenger receptor class B, type I (SR-BI) mediates the selective uptake of lipids from high dens... more Scavenger receptor class B, type I (SR-BI) mediates the selective uptake of lipids from high density lipoproteins and is expressed in several types of tissues. However, to date little is known about its role in adipocytes. In this study, we investigated the cellular distribution of SR-BI in 3T3-L1 adipocytes and its regulation by hormones known to increase lipid storage such as angiotensin II (Ang II) and insulin. SR-BI was mainly distributed in the cytoplasm as determined by laser-scanning confocal analysis of the immunofluorescence labeling of SR-BI or the study of an enhanced green fluorescent protein-tagged SR-BI fusion protein. Exposure of cells to either insulin or Ang II (1-2 h) induced the mobilization of SR-BI from intracellular pools to the plasma membrane. This was further confirmed by Western blotting on purified plasma membrane and by fluorescence-activated cell sorter analysis of the SR-BI receptor. Similar results were also observed in primary adipocytes. We also demonstrated that, in the presence of either insulin or Ang II, SR-BI translocation to the cell membrane is functional, because insulin and Ang II induced a significant increase in the high density lipoprotein-delivered 22-(N-7-nitrobenz-2-oxa-1,3-diazo-4-yl)amino-23,24-bisnor-5-cholen-3-ol uptake and in total cholesterol content. These data demonstrate that SR-BI can be acutely mobilized from intracellular stores to the cell surface by insulin or Ang II, two hormones that exert lipogenic effects in adipocytes. This suggests that SR-BI might participate in the storage of lipids in the adipose tissue.
The Journal of clinical endocrinology and metabolism, 2008
Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by ne... more Berardinelli-Seip congenital lipodystrophy (BSCL) is a rare recessive disease characterized by near absence of adipose tissue, resulting in severe dyslipidemia and insulin resistance. In most reported cases, BSCL is due to alterations in either seipin, of unknown function, or 1-acylglycerol-3-phosphate acyltransferase-beta (AGPAT2), which catalyzes the formation of phosphatidic acid.
Diabetes & Metabolism, 2010
ment la sensibilité à l'insuline pourrait déboucher sur de nouvelles pistes thérapeutiques. COMMU... more ment la sensibilité à l'insuline pourrait déboucher sur de nouvelles pistes thérapeutiques. COMMUNICATIONS ORALES Signalisation et insulinorésistance O43 La compartimentalisation des sub-domaines de la membrane plasmique contribue à des mécanismes d'action des céramides différents sur la voie de signalisation de l'insuline
Diabetes, 1997
Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act ... more Thiazolidinediones are potent antidiabetic compounds, in both animal and human models, which act by enhancing peripheral sensitivity to insulin. Thiazolidinediones are high-affinity ligands for peroxisome proliferator-activated receptor-7, a key factor for adipocyte differentiation, and they are efficient promoters of adipocyte differentiation in vitro. Thus, it could be questioned whether a thiazolidinedione therapy aimed at improving insulin sensitivity would promote the recruitment of new adipocytes in vivo. To address this problem, we have studied the in vivo effect of pioglitazone on glucose metabolism and gene expression in the adipose tissue of an animal model of obesity with insulin resistance, the obese Zucker (fa/fa) rat. Pioglitazone markedly improves insulin action in the obese Zucker (fa/fa) rat, but doubles its weight gain after 4 weeks of treatment. The drug induces a large increase of glucose utilization in adipose tissue, where it stimulates the expression of genes involved in lipid metabolism such as the insulinresponsive GLUT, fatty acid synthase, and phosphoenolpyruvate carboxykinase genes, but decreases the expression of the ob gene. These changes are related to both an enhanced adipocyte differentiation, as shown by the large increase in the number of small adipocytes in the retroperitoneal fat pad, and a direct effect of pioglitazone on specific gene expression (phosphoenolpyruvate carboxykinase and ob genes) in mature adipocytes.
Uploads
Papers by Isabelle Dugail