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1. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A1

Author

Giulia Salvatore, Nathalie Bernoud-Hubac, Nathalie Bissay, Cyrille Debard, Patricia Daira, Emmanuelle Meugnier, Fabienne Proamer, Daniel Hanau, Hubert Vidal, Maurizio Aricò, Christine Delprat, and Karène Mahtouk

Subjects
immunology, monocytes, inflammation, microarrays, lipidomics, interleukin 17A, Biochemistry, QD415-436
Abstract

Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2–12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-α, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells “foamy DCs” and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A.

Published
2015
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2. Evaluation of Three Devices for the Isolation of the Stromal Vascular Fraction from Adipose Tissue and for ASC Culture: A Comparative Study

Author

Jonathan Rodriguez, Anne-Sophie Pratta, Nacira Abbassi, Hugo Fabre, Fanny Rodriguez, Cyrille Debard, Jacqueline Adobati, Fabien Boucher, Frédéric Mallein-Gerin, Céline Auxenfans, Odile Damour, and Ali Mojallal

Subjects
Internal medicine, RC31-1245
Abstract

Adipose-derived stem/stromal cells (ASCs) reside in the stromal vascular fraction (SVF) of adipose tissue (AT) and can be easily isolated. However, extraction of the SVF from lipoaspirate is a critical step in generating ASC, and semiautomated devices have been developed to enhance the efficacy and reproducibility of the outcomes and to decrease manipulation and contamination. In this study, we compared the reference method used in our lab for SVF isolation from lipoaspirate, with three medical devices: GID SVF-1™, Puregraft™, and Stem.pras®. Cell yield and their viability were evaluated as well as their phenotype with flow cytometry. Further on, we determined their proliferative potential using population doublings (PD), PD time (PDT), and clonogenicity assay (CFU-F). Finally, we checked their genetic stability using RT-qPCR for TERT mRNA assay and karyotyping as well as their multilineage potential including adipogenic, chondrogenic, and osteogenic differentiation. Our results demonstrate that all the devices allow the production of SVF cells with consistent yield and viability, in less time than the reference method. Expanded cells from the four methods showed no significant differences in terms of phenotype, proliferation capabilities, differentiation abilities, and genetic stability.

Published
2017
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3. Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells

Author

Manar Awada, Christophe O. Soulage, Anne Meynier, Cyrille Debard, Pascale Plaisancié, Bérengère Benoit, Grégory Picard, Emmanuelle Loizon, Marie-Agnès Chauvin, Monique Estienne, Noël Peretti, Michel Guichardant, Michel Lagarde, Claude Genot, and Marie-Caroline Michalski

Subjects
nutrition, polyunsaturated fatty acids, lipid peroxidation, 4-hydroxy-2-alkenals, intestine, Biochemistry, QD415-436
Abstract

Dietary intake of long-chain n-3 PUFA is now widely advised for public health and in medical practice. However, PUFA are highly prone to oxidation, producing potentially deleterious 4-hydroxy-2-alkenals. Even so, the impact of consuming oxidized n-3 PUFA on metabolic oxidative stress and inflammation is poorly described. We therefore studied such effects and hypothesized the involvement of the intestinal absorption of 4-hydroxy-2-hexenal (4-HHE), an oxidized n-3 PUFA end-product. In vivo, four groups of mice were fed for 8 weeks high-fat diets containing moderately oxidized or unoxidized n-3 PUFA. Other mice were orally administered 4-HHE and euthanized postprandially versus baseline mice. In vitro, human intestinal Caco-2/TC7 cells were incubated with 4-hydroxy-2-alkenals. Oxidized diets increased 4-HHE plasma levels in mice (up to 5-fold, P < 0.01) compared with unoxidized diets. Oxidized diets enhanced plasma inflammatory markers and activation of nuclear factor kappaB (NF-κB) in the small intestine along with decreasing Paneth cell number (up to −19% in the duodenum). Both in vivo and in vitro, intestinal absorption of 4-HHE was associated with formation of 4-HHE-protein adducts and increased expression of glutathione peroxidase 2 (GPx2) and glucose-regulated protein 78 (GRP78). Consumption of oxidized n-3 PUFA results in 4-HHE accumulation in blood after its intestinal absorption and triggers oxidative stress and inflammation in the upper intestine.

Published
2012
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4. Insulin resistance is associated with MCP1-mediated macrophage accumulation in skeletal muscle in mice and humans.

Author

David Patsouris, Jingwei-Ji Cao, Guillaume Vial, Amelie Bravard, Etienne Lefai, Annie Durand, Christine Durand, Marie-Agnés Chauvin, Fabienne Laugerette, Cyrille Debard, Marie-Caroline Michalski, Martine Laville, Hubert Vidal, and Jennifer Rieusset

Subjects
Medicine, Science
Abstract

Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFα expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.

Published
2014
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6. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance.

Author

Serenella Salinari, Cyrille Debard, Alessandro Bertuzzi, Christine Durand, Paul Zimmet, Hubert Vidal, and Geltrude Mingrone

Subjects
Medicine, Science
Abstract

Two recent studies demonstrated that bariatric surgery induced remission of type 2 diabetes very soon after surgery and far too early to be attributed to weight loss. In this study, we sought to explore the mechanism/s of this phenomenon by testing the effects of proteins from the duodenum-jejunum conditioned-medium (CM) of db/db or Swiss mice on glucose uptake in vivo in Swiss mice and in vitro in both Swiss mice soleus and L6 cells. We studied the effect of sera and CM proteins from insulin resistant (IR) and insulin-sensitive subjects on insulin signaling in human myoblasts.db/db proteins induced massive IR either in vivo or in vitro, while Swiss proteins did not. In L6 cells, only db/db proteins produced a noticeable increase in basal (473)Ser-Akt phosphorylation, lack of GSK3β inhibition and a reduced basal (389)Thr-p70-S6K1 phosphorylation. Human IR serum markedly increased basal (473)Ser-Akt phosphorylation in a dose-dependent manner. Human CM IR proteins increased by about twofold both basal and insulin-stimulated (473)Ser-Akt. Basal (9)Ser-GSK3β phosphorylation was increased by IR subjects serum with a smaller potentiating effect of insulin.These findings show that jejunal proteins either from db/db mice or from insulin resistant subjects impair muscle insulin signaling, thus inducing insulin resistance.

Published
2013
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7. The eicosapentaenoic acid metabolite 15-deoxy-δ(12,14)-prostaglandin J3 increases adiponectin secretion by adipocytes partly via a PPARγ-dependent mechanism.

Author

Jennifer Lefils-Lacourtablaise, Mairobys Socorro, Alain Géloën, Patricia Daira, Cyrille Debard, Emmanuelle Loizon, Michel Guichardant, Zury Dominguez, Hubert Vidal, Michel Lagarde, and Nathalie Bernoud-Hubac

Subjects
Medicine, Science
Abstract

The intake of ω-3 polyunsaturated fatty acids (PUFAs), which are abundant in marine fish meat and oil, has been shown to exert many beneficial effects. The mechanisms behind those effects are numerous, including interference with the arachidonic acid cascade that produces pro-inflammatory eicosanoids, formation of novel bioactive lipid mediators, and change in the pattern of secreted adipocytokines. In our study, we show that eicosapentaenoic acid (EPA) increases secreted adiponectin from 3T3-L1 adipocytes and in plasma of mice as early as 4 days after initiation of an EPA-rich diet. Using 3T3-L1 adipocytes, we report for the first time that 15-deoxy-δ(12,14)-PGJ3 (15d-PGJ3), a product of EPA, also increases the secretion of adiponectin. We demonstrate that the increased adiponectin secretion induced by 15d-PGJ3 is partially peroxisome proliferator-activated receptor-gamma (PPAR-γ)-mediated. Finally, we show that 3T3-L1 adipocytes can synthesize 15d-PGJ3 from EPA. 15d-PGJ3 was also detected in adipose tissue from EPA-fed mice. Thus, these studies provide a novel mechanism(s) for the therapeutic benefits of ω-3 polyunsaturated fatty acids dietary supplementation.

Published
2013
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8. Gender differences in transcriptional signature of developing rat testes and ovaries following embryonic exposure to 2,3,7,8-TCDD.

Author

Solange Magre, Diane Rebourcet, Muhammad Ishaq, Richard Wargnier, Cyrille Debard, Emmanuelle Meugnier, Hubert Vidal, Joëlle Cohen-Tannoudji, and Brigitte Le Magueresse-Battistoni

Subjects
Medicine, Science
Abstract

Dioxins are persistent organic pollutants interfering with endocrine systems and causing reproductive and developmental disorders. The objective of our project was to determine the impact of an in utero exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on reproductive function of male and female offspring in the rat with a special emphasis on the immature period. We used a low dose of TCDD (unique exposure by oral gavage of 200 ng/kg at 15.5 days of gestation) in order to mirror a response to an environmental dose of TCDD not altering fertility of the progeny. We choose a global gene expression approach using Affymetrix microarray analysis, and testes of 5 days and ovaries of 14 days of age. Less than 1% of the expressed genes in gonads were altered following embryonic TCDD exposure; specifically, 113 genes in ovaries and 56 in testes with 7 genes common to both sex gonads. It included the repressor of the aryl hydrocarbon receptor (Ahrr), the chemokines Ccl5 and Cxcl4 previously shown to be regulated by dioxin in testis, Pgds2/Hpgds and 3 others uncharacterized. To validate and extend the microarray data we realized real-time PCR on gonads at various developmental periods of interest (from 3 to 25 days for ovaries, from 5 to the adult age for testes). Overall, our results evidenced that both sex gonads responded differently to TCDD exposure. For example, we observed induction of the canonic battery of TCDD-induced genes coding enzymes of the detoxifying machinery in ovaries aged of 3-14 days of age (except Cyp1a1 induced at 3-10 days) but not in testes of 5 days (except Ahrr). We also illustrated that inflammatory pathway is one pathway activated by TCDD in gonads. Finally, we identified several new genes targeted by TCDD including Fgf13 in testis and one gene, Ptgds2/Hpgds regulated in the two sex gonads.

Published
2012
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9. Evaluation of Three Devices for the Isolation of the Stromal Vascular Fraction from Adipose Tissue and for ASC Culture: A Comparative Study

Author

Ali Mojallal, F. Boucher, Jonathan Rodriguez, Cyrille Debard, Hugo Fabre, Odile Damour, Nacira Abbassi, Anne-Sophie Pratta, Fanny Rodriguez, Frédéric Mallein-Gerin, Jacqueline Adobati, Céline Auxenfans, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Service Chirurgie Plast Esthétique et Reconstructrice, Hospices Civils de Lyon (HCL), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Banque de tissus et de cellules, Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), chirurgie plastique, reconstructrice et esthétique, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, lcsh:Internal medicine, Pathology, medicine.medical_specialty, Stromal cell, Article Subject, Population, Adipose tissue, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Flow cytometry, 03 medical and health sciences, medicine, lcsh:RC31-1245, education, Molecular Biology, ComputingMilieux_MISCELLANEOUS, education.field_of_study, medicine.diagnostic_test, Cell Biology, Stromal vascular fraction, Chondrogenesis, Phenotype, Cell biology, 030104 developmental biology, Adipogenesis, Research Article
Abstract

Adipose-derived stem/stromal cells (ASCs) reside in the stromal vascular fraction (SVF) of adipose tissue (AT) and can be easily isolated. However, extraction of the SVF from lipoaspirate is a critical step in generating ASC, and semiautomated devices have been developed to enhance the efficacy and reproducibility of the outcomes and to decrease manipulation and contamination. In this study, we compared the reference method used in our lab for SVF isolation from lipoaspirate, with three medical devices: GID SVF-1™, Puregraft™, and Stem.pras®. Cell yield and their viability were evaluated as well as their phenotype with flow cytometry. Further on, we determined their proliferative potential using population doublings (PD), PD time (PDT), and clonogenicity assay (CFU-F). Finally, we checked their genetic stability using RT-qPCR for TERT mRNA assay and karyotyping as well as their multilineage potential including adipogenic, chondrogenic, and osteogenic differentiation. Our results demonstrate that all the devices allow the production of SVF cells with consistent yield and viability, in less time than the reference method. Expanded cells from the four methods showed no significant differences in terms of phenotype, proliferation capabilities, differentiation abilities, and genetic stability.

Published
2017
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10. Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells

Author

Grégory Picard, Marie-Agnès Chauvin, Emmanuelle Loizon, Monique Estienne, Michel Lagarde, Anne Meynier, Noël Peretti, Pascale Plaisancié, Michel Guichardant, Marie-Caroline Michalski, Bérengère Benoit, Claude Genot, Manar Awada, Cyrille Debard, Christophe O. Soulage, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Michalski, Marie-Caroline

Subjects
Male, MESH: Inflammation, MESH: Oxidation-Reduction, 4-hydroxy-2-alkenals, GPX2, 030309 nutrition & dietetics, métabolisme des lipides, MESH: Heat-Shock Proteins, medicine.disease_cause, Biochemistry, Intestinal absorption, MESH: Lipid Peroxidation, Lipid peroxidation, Mice, chemistry.chemical_compound, absorption digestive, Endocrinology, MESH: Fatty Acids, Omega-3, MESH: Animals, Intestinal Mucosa, Endoplasmic Reticulum Chaperone BiP, Research Articles, Heat-Shock Proteins, chemistry.chemical_classification, 0303 health sciences, MESH: Oxidative Stress, peroxydation lipidique, Glutathione peroxidase, lipid peroxidation, 3. Good health, medicine.anatomical_structure, nutrition, Alimentation et Nutrition, peroxydation des lipides, MESH: Caco-2 Cells, medicine.symptom, Oxidation-Reduction, nutrition humaine, MESH: Intestines, polyunsaturated fatty acids, medicine.medical_specialty, MESH: Intestinal Absorption, Inflammation, QD415-436, Biology, Diet, High-Fat, acide gras polyinsaturé n 3, 03 medical and health sciences, physiologie digestive, MESH: Mice, Inbred C57BL, Internal medicine, Fatty Acids, Omega-3, inflammation intestinale, medicine, Animals, Humans, Food and Nutrition, nutrition, polyunsaturated fatty acids, lipid peroxidation, 4-hydroxy-2-alkenals, intestine, MESH: Mice, intestine, 030304 developmental biology, Aldehydes, Glutathione Peroxidase, MESH: Humans, MESH: Biological Markers, Cell Biology, Small intestine, MESH: Male, Mice, Inbred C57BL, Oxidative Stress, MESH: Diet, High-Fat, Intestinal Absorption, chemistry, Paneth cell, MESH: Glutathione Peroxidase, MESH: Aldehydes, Caco-2 Cells, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Biomarkers, Oxidative stress, inflammation de l'intestin
Abstract

ISI Document Delivery No.: 004QQTimes Cited: 0Cited Reference Count: 46Cited References: Pillon Nicolas J., 2011, CHEMICAL RESEARCH IN TOXICOLOGY, V24, P752Awada, Manar Soulage, Christophe O. Meynier, Anne Debard, Cyrille Plaisancie, Pascale Benoit, Berengere Picard, Gregory Loizon, Emmanuelle Chauvin, Marie-Agnes Estienne, Monique Peretti, Noel Guichardant, Michel Lagarde, Michel Genot, Claude Michalski, Marie-CarolineFrench National Research Agency (ANR)[ANR-08-ALIA-002]; ANRThis work was supported by the French National Research Agency (ANR) Grant ANR-08-ALIA-002, AGECANINOX project.M. Awada acknowledges her PhD grant from ANR. The authors thank Lucie Ribourg and Michele Viau for their work on oil mixtures. Patricia Daira is acknowledged for her help with the 4-hydroxy-2-alkenal assay. The authors thank Jean-Michel Chardigny for useful discussions. Isabelle Jouanin (Plateforme AXIOM-MetaToul, Toulouse) is acknowledged for the synthesis of internal standards to measure 4-hydroxyl-2-alkenals in fat. Yvonne Masson is acknowledged for revising the English-language manuscript.Amer soc biochemistry molecular biology incBethesda[Awada, Manar; Plaisancie, Pascale; Estienne, Monique; Michalski, Marie-Caroline] INRA, CarMeN Lab U1235, F-69621 Villeurbanne, France. [Awada, Manar; Soulage, Christophe O.; Guichardant, Michel; Lagarde, Michel; Michalski, Marie-Caroline] Inst Natl Sci Appl, IMBL, F-69621 Villeurbanne, France. [Meynier, Anne; Genot, Claude] INRA, Biopolymeres Interact Assemblages UR1268, F-44300 Nantes, France. [Debard, Cyrille; Chauvin, Marie-Agnes] INSERM, U1060, CarMeN Lab, F-69921 Oullins, France. [Benoit, Berengere; Picard, Gregory; Loizon, Emmanuelle; Peretti, Noel; Michalski, Marie-Caroline] Univ Lyon 1, F-69622 Villeurbanne, France.marie-caroline.michalski@insa-lyon.fr; International audience; Dietary intake of long-chain n-3 PUFA is now widely advised for public health and in medical practice. However, PUFA are highly prone to oxidation, producing potentially deleterious 4-hydroxy-2-alkenals. Even so, the impact of consuming oxidized n-3 PUFA on metabolic oxidative stress and inflammation is poorly described. We therefore studied such effects and hypothesized the involvement of the intestinal absorption of 4-hydroxy-2-hexenal (4-HHE), an oxidized n-3 PUFA end-product. In vivo, four groups of mice were fed for 8 weeks high-fat diets containing moderately oxidized or unoxidized n-3 PUFA. Other mice were orally administered 4-HHE and euthanized postprandially versus baseline mice. In vitro, human intestinal Caco-2/TC7 cells were incubated with 4-hydroxy-2-alkenals. Oxidized diets increased 4-HHE plasma levels in mice (up to 5-fold, P < 0.01) compared with unoxidized diets. Oxidized diets enhanced plasma inflammatory markers and activation of nuclear factor kappaB (NF-κB) in the small intestine along with decreasing Paneth cell number (up to -19% in the duodenum). Both in vivo and in vitro, intestinal absorption of 4-HHE was associated with formation of 4-HHE-protein adducts and increased expression of glutathione peroxidase 2 (GPx2) and glucose-regulated protein 78 (GRP78). Consumption of oxidized n-3 PUFA results in 4-HHE accumulation in blood after its intestinal absorption and triggers oxidative stress and inflammation in the upper intestine.

Published
2012
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11. Tpl2 Kinase Is Upregulated in Adipose Tissue in Obesity and May Mediate Interleukin-1β and Tumor Necrosis Factor-α Effects on Extracellular Signal–Regulated Kinase Activation and Lipolysis

Author

Cyrille Debard, Yannick Le Marchand-Brustel, Albert Tran, Mireille Cormont, Martine Laville, Philippe Gual, Hubert Vidal, T Grémeaux, Jennifer Jager, Jean-François Tanti, Stéphanie Bonnafous, and Teresa Gonzalez

Subjects
Male, medicine.medical_specialty, FGF21, Lipolysis, Endocrinology, Diabetes and Metabolism, Adipose tissue macrophages, Interleukin-1beta, Mice, Obese, Adipose tissue, Biology, Proinflammatory cytokine, Mice, chemistry.chemical_compound, Thinness, Mice, Inbred NOD, 3T3-L1 Cells, Proto-Oncogene Proteins, Adipocyte, Internal medicine, Adipocytes, Internal Medicine, medicine, Animals, Humans, Mitogen-Activated Protein Kinase 3, MAP kinase kinase kinase, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, I-Kappa-B Kinase, Cell Differentiation, Fasting, MAP Kinase Kinase Kinases, I-kappa B Kinase, Obesity, Morbid, Up-Regulation, Enzyme Activation, Mice, Inbred C57BL, Insulin receptor, Endocrinology, chemistry, Cancer research, biology.protein, Original Article, Signal Transduction
Abstract

OBJECTIVE Activation of extracellular signal–regulated kinase-(ERK)-1/2 by cytokines in adipocytes is involved in the alterations of adipose tissue functions participating in insulin resistance. This study aims at identifying proteins regulating ERK1/2 activity, specifically in response to inflammatory cytokines, to provide new insights into mechanisms leading to abnormal adipose tissue function. RESEARCH DESIGN AND METHODS Kinase activities were inhibited with pharmacological inhibitors or siRNA. Lipolysis was monitored through glycerol production. Gene expression in adipocytes and adipose tissue of obese mice and subjects was measured by real-time PCR. RESULTS IκB kinase-(IKK)-β inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1β and tumor necrosis factor (TNF)-α but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKβ regulated a MAP kinase kinase kinase (MAP3K) involved in ERK1/2 activation induced by inflammatory cytokines. We show that the MAP3K8 called Tpl2 was expressed in adipocytes and that IL-1β and TNF-α activated Tpl2 and regulated its expression through an IKKβ pathway. Pharmacological inhibition or silencing of Tpl2 prevented MEK/ERK1/2 activation by these cytokines but not by insulin, demonstrating its involvement in ERK1/2 activation specifically in response to inflammatory stimuli. Importantly, Tpl2 was implicated in cytokine-induced lipolysis and in insulin receptor substrate-1 serine phosphorylation. Tpl2 mRNA expression was upregulated in adipose tissue of obese mice and patients and correlated with TNF-α expression. CONCLUSIONS Tpl2 is selectively involved in inflammatory cytokine–induced ERK1/2 activation in adipocytes and is implicated in their deleterious effects on adipocyte functions. The deregulated expression of Tpl2 in adipose tissue suggests that Tpl2 may be a new actor in adipose tissue dysfunction in obesity.

Published
2009
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12. Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle

Author

Etienne Lefai, Vanessa Euthine, Virginie Lecomte, Sophie Rome, Cyrille Debard, Hubert Vidal, Jennifer Rieusset, Emmanuelle Meugnier, meugnier, emmanuelle, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), This work was supported in part by a research grant from the French National Program of Research on Diabetes (PNRD, ROSIH project)., Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vericel, Evelyne, and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)

Subjects
MESH: Oxidation-Reduction, Cell Extracts, Male, Microarray, Physiology, [SDV]Life Sciences [q-bio], MESH: Glycogen, Muscle Fibers, Skeletal, MESH: Base Sequence, MESH: Protein Isoforms, 0302 clinical medicine, Transcription (biology), MESH: Cell Extracts, Protein Isoforms, Gene Regulatory Networks, Promoter Regions, Genetic, transcription factor, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, MESH: Gene Regulatory Networks, Oligonucleotide Array Sequence Analysis, MESH: Chromatin Immunoprecipitation, MESH: Muscle, Skeletal, 0303 health sciences, MESH: Muscle Fibers, Skeletal, MESH: Immunoblotting, adenovirus, MESH: Transcription Factors, MESH: Gene Expression Regulation, MESH: Glucose, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Female, lipids (amino acids, peptides, and proteins), Sterol Regulatory Element Binding Protein 1, Oxidation-Reduction, Glycogen, MESH: Cells, Cultured, Gene isoform, Chromatin Immunoprecipitation, Immunoblotting, Molecular Sequence Data, Biology, MESH: Sterol Regulatory Element Binding Protein 1, 03 medical and health sciences, MESH: Promoter Regions, Genetic, Genetics, Humans, human, RNA, Messenger, skeletal muscle, Muscle, Skeletal, Gene, Transcription factor, MESH: RNA, Messenger, 030304 developmental biology, promoter, MESH: Humans, MESH: Molecular Sequence Data, Base Sequence, Promoter, Molecular biology, MESH: Male, DNA binding motif, Sterol regulatory element-binding protein, DNA binding site, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Glucose, Gene Expression Regulation, MESH: Oligonucleotide Array Sequence Analysis, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Transcription Factors
Abstract

International audience; In this study we have identified the target genes of sterol regulatory element binding protein (SREBP)-1a and SREBP-1c in primary cultures of human skeletal muscle cells, using adenoviral vectors expressing the mature nuclear form of human SREBP-1a or SREBP-1c combined with oligonucleotide microarrays. Overexpression of SREBP-1a led to significant changes in the expression of 1,315 genes (655 upregulated and 660 downregulated), whereas overexpression of SREBP-1c modified the mRNA level of 514 genes (310 upregulated and 204 downregulated). Gene ontology analysis indicated that in human muscle cells SREBP-1a and -1c are involved in the regulation of a large number of genes that are at the crossroads of different functional pathways, several of which are not directly connected with cholesterol and lipid metabolism. Six hundred fifty-two of all genes identified to be differentially regulated on SREBP overexpression had a sterol regulatory element (SRE) motif in their promoter sequences. Among these, 429 were specifically regulated by SREBP-1a, 69 by SREBP-1c, and 154 by both 1a and 1c. Because both isoforms recognize the same binding motif, we determined whether some of these functional differences could depend on the environment of the SRE motifs in the promoters. Results from promoter analysis showed that different combinations of transcription factor binding sites around the SRE binding motifs may determine regulatory networks of transcription that could explain the superposition of lipid and cholesterol metabolism with various other pathways involved in adaptive responses to stress like hypoxia and heat shock, or involvement in the immune response.

Published
2008
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13. Isoform-specific defects of insulin stimulation of Akt/protein kinase B (PKB) in skeletal muscle cells from type 2 diabetic patients

Author

Emmanuel Disse, Hubert Vidal, Martine Laville, Sara Fröjdö, Delphine Cozzone, Luciano Pirola, and Cyrille Debard

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, AKT1, AKT2, Biology, AKT3, Phosphoserine, Insulin resistance, Reference Values, Internal medicine, Phosphoprotein Phosphatases, Internal Medicine, medicine, Humans, Insulin, RNA, Messenger, Phosphorylation, Muscle, Skeletal, Protein kinase B, Akt/PKB signaling pathway, Nuclear Proteins, Skeletal muscle, Middle Aged, medicine.disease, Enzyme Activation, Isoenzymes, Phosphothreonine, medicine.anatomical_structure, Endocrinology, Diabetes Mellitus, Type 2, Female, Proto-Oncogene Proteins c-akt
Abstract

The serine/threonine kinase Akt/protein kinase B (PKB) is required for the metabolic actions of insulin. Controversial data have been reported regarding Akt defective activation in the muscle of type 2 diabetic patients. Because three Akt isoforms exist, each having a distinct physiological role, we investigated the contribution of isoform-specific defects to insulin signalling in human muscle.The phosphorylation pattern and kinase activity of each Akt isoform were compared in primary myotubes from healthy control participants and type 2 diabetic patients. Phosphorylation of Ser(473) and of Thr(308) in each isoform was determined after immunoprecipitation in myotubes treated or not with insulin.Muscle cells from diabetic patients displayed defective insulin action and a drastic reduction of insulin-stimulated activity of all Akt isoforms. This was associated with specific defects of their phosphorylation pattern in response to insulin, with impaired Akt2- (and to a lower extent Akt3-) Ser(473) phosphorylation, and with altered Akt1-Thr(308) phosphorylation. These defects were not due to faulty phosphoinositide-dependent protein kinase 1 (PDK1) production or activation. Rather, we found higher levels of the Akt2-Ser(473)-specific protein phosphatase PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1) in muscle from diabetic patients, which may contribute to the alteration of Akt2-Ser(473) phosphorylation.These results suggest that several mechanisms affecting Akt isoforms, including deregulated production of PHLPP1, could underlie the alterations of skeletal muscle insulin signalling in type 2 diabetes. Taking into account the recently described isoform-specific metabolic functions of Akt, our results provide mechanistic insight that may contribute to the defective regulation of glucose and lipid metabolisms in the muscle of diabetic patients.

Published
2008
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14. Human monocyte-derived dendritic cells turn into foamy dendritic cells with IL-17A

Author

Fabienne Proamer, Karène Mahtouk, Emmanuelle Meugnier, Maurizio Aricò, Christine Delprat, Cyrille Debard, Daniel Hanau, Nathalie Bernoud-Hubac, Nathalie Bissay, Giulia Salvatore, Patricia Daira, Hubert Vidal, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), (France) CNRS, INSERM, Universite de Lyon 1, Institut Universitaire de France, Fondation pour l'Innovation et la Valorisation en Infectiologie, ANR Microbiologie-Immunologie-Environnement, LyonBiopole, Etablissement Francais du Sang EFS-Alsace, ARMESA (Association de Recherche et de Developpement en Medecine et Sante Publique), (Italy) Associazione Italiana Ricerca Istiocitosi (AIRI), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Analyses de Biologie Médicale (LABM), Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS Alsace, Biologie des Cellules Dendritiques Humaines, EFS-Cancéropôle du Grand Est-Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Onco-Hematology, A.Meyer Children's Hospital, Université de Lyon, Institut de recherche en biothérapie (IRB), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Delprat, Christine, and Mahtouk, Karène

Subjects
Macrophages/immunology/metabolism, Cellular differentiation, [SDV]Life Sciences [q-bio], immunology, monocytes, inflammation, microarrays, lipidomics, interleukin 17A, lipid, immunometabolism, Cell Differentiation/genetics, Lipid Droplets/immunology/metabolism, Inflammation, Foam Cells/metabolism, Biology, Biochemistry, Interleukin-17/genetics/immunology/*metabolism, Proinflammatory cytokine, chemistry.chemical_compound, Cell Proliferation/genetics, Endocrinology, Lipid droplet, medicine, Oil Red O, Humans, T-Lymphocytes/immunology/metabolism, cytokine proinflammatoire, pathogénèse, Liver X receptor, maladie inflammatoire, ComputingMilieux_MISCELLANEOUS, Monocytes/immunology/metabolism, Atherosclerosis/immunology/*metabolism/pathology, Fatty Acids/*metabolism, Lipid metabolism, Cell Biology, Dendritic Cells/immunology/*metabolism, 3. Good health, Cell biology, chemistry, Gene Expression Regulation, Immunology, Orphan Nuclear Receptors/biosynthesis/metabolism, lipids (amino acids, peptides, and proteins), Interleukin 17, medicine.symptom, Lipid Metabolism/immunology
Abstract

International audience; Interleukin 17A (IL-17A) is a proinflammatory cytokine involved in the pathogenesis of chronic inflammatory diseases. In the field of immunometabolism, we have studied the impact of IL-17A on the lipid metabolism of human in vitro-generated monocyte-derived dendritic cells (DCs). Microarrays and lipidomic analysis revealed an intense remodeling of lipid metabolism induced by IL-17A in DCs. IL-17A increased 2-12 times the amounts of phospholipids, cholesterol, triglycerides, and cholesteryl esters in DCs. Palmitic (16:0), stearic (18:0), and oleic (18:ln-9c) acid were the main fatty acid chains present in DCs. They were strongly increased in response to IL-17A while their relative proportion remained unchanged. Capture of extracellular lipids was the major mechanism of lipid droplet accumulation, visualized by electron microscopy and Oil Red O staining. Besides this foamy phenotype, IL-17A induced a mixed macrophage-DC phenotype and expression of the nuclear receptor NR1H3/liver X receptor-alpha, previously identified in the context of atherosclerosis as the master regulator of cholesterol homeostasis in macrophages. These IL-17A-treated DCs were as competent as untreated DCs to stimulate allogeneic naive T-cell proliferation. Following this first characterization of lipid-rich DCs, we propose to call these IL-17A-dependent cells "foamy DCs" and discuss the possible existence of foamy DCs in atherosclerosis, a metabolic and inflammatory disorder involving IL-17A.

Published
2015
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15. Increased adiponectin receptor-1 expression in adipose tissue of impaired glucose-tolerant obese subjects during weight loss

Author

Hubert Vidal, Cyrille Debard, Minji Kim, Karine Clément, Mustapha Maachi, Eric Bruckert, Bernard Hainque, Jacqueline Capeau, Jean-Philippe Bastard, and Emmanuelle Loizon

Subjects
Adult, Male, medicine.medical_specialty, Diet, Reducing, endocrine system diseases, Endocrinology, Diabetes and Metabolism, food.diet, Gene Expression, Peroxisome proliferator-activated receptor, Adipose tissue, Receptors, Cell Surface, Biology, Body Mass Index, Impaired glucose tolerance, Endocrinology, food, Weight loss, Internal medicine, Glucose Intolerance, Weight Loss, medicine, Humans, Obesity, RNA, Messenger, chemistry.chemical_classification, Adiponectin receptor 1, Adiponectin, Reverse Transcriptase Polymerase Chain Reaction, nutritional and metabolic diseases, General Medicine, medicine.disease, PPAR gamma, Very low calorie diet, Adipose Tissue, chemistry, Female, Receptors, Adiponectin, medicine.symptom, Body mass index, hormones, hormone substitutes, and hormone antagonists
Abstract

Objective: To investigate the mRNA expression of adiponectin, AdipoR1 and AdipoR2, the two recently cloned adiponectin receptors and peroxisome proliferator activated receptor (PPAR)γ2 in adipose tissue of obese individuals before and during a very low calorie diet (VLCD) inducing weight loss. Methods: Twenty-three non-diabetic obese subjects with normal (NGT, n=11) or impaired glucose tolerance (IGT, n=12) (age, 47±3 years; body mass index, 39.3±1.3 kg/m2) were studied before and after a 3-week 3.9 MJ diet daily without exercise. mRNA levels of nine IGT and six NGT subjects were measured by real-time PCR in s.c. abdominal adipose tissue. Results: Metabolic parameters and insulin sensitivity were improved by VLCD in the IGT group, but minimally affected in the NGT group. VLCD increased expression of AdipoR1 in the IGT (P=0.02), but not in the NGT group. Adiponectin, AdipoR2 and PPARγ2 mRNA levels did not change during VLCD in any group. In the IGT, but not in the NGT group, AdipoR1 and AdipoR2 expressions were positively related to that of PPARγ2 and, after VLCD, AdipoR1 and AdipoR2 expressions were positively related to each other and to that of adiponectin. Conclusion: In the NGT group, the 3-week VLCD inducing weight loss did not modify metabolic parameters, insulin sensitivity and the expression of the adiponectin system in adipose tissue. By contrast, in the IGT group, AdipoR1 expression increased and we found a coordinate regulation of the expression of adiponectin and its receptors. These modifications could participate, through adiponectin action on adipocytes, to the improved metabolic parameters observed in IGT subjects.

Published
2006
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16. Pasture v. standard dairy cream in high-fat diet-fed mice: improved metabolic outcomes and stronger intestinal barrier

Author

Alain Géloën, Bérengère Benoit, Hubert Vidal, Cyrille Debard, Jacques Bodennec, Olivier Cousin, Monique Estienne, Emmanuelle Loizon, Fabienne Laugerette, Pascale Plaisancié, Emmanuelle Meugnier, Marie-Caroline Michalski, Patricia Daira, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Sodiaal-Candia RD, Institut Multidisciplinaire de Biochimie des Lipides (IMBL), Covalab-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Sodiaal Candia R&D, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Sciences Po Bordeaux - Institut d'études politiques de Bordeaux (IEP Bordeaux), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Covalab

Subjects
Male, Panniculitis, Milk/adverse effects/chemistry/secretion, 030309 nutrition & dietetics, Conjugated linoleic acid, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Adipose tissue, White adipose tissue, Inbred C57BL, Jejunum, chemistry.chemical_compound, Mice, Random Allocation, Functional Food, Lactation, Food science, Intestinal Mucosa, Animal Husbandry, ComputingMilieux_MISCELLANEOUS, Intestinal Mucosa/immunology/metabolism/pathology/physiopathology, 2. Zero hunger, Hypertriglyceridemia, 0303 health sciences, Nutrition and Dietetics, Hypertriglyceridemia/etiology/prevention & control, Chemistry, Aerial/chemistry/growth & development, Intestinal epithelium, Poaceae/chemistry/growth & development, medicine.anatomical_structure, Milk, Liver, Adipose Tissue, Female, Cattle/*physiology, Liver/metabolism, medicine.medical_specialty, Adipose Tissue, White, High-Fat/adverse effects, Context (language use), Diet, High-Fat, Poaceae, Functional Food/analysis, Dairy Products/adverse effects/analysis, 03 medical and health sciences, Internal medicine, medicine, Panniculitis/etiology/*prevention & control, Diet/*veterinary, Animals, Obesity, 030304 developmental biology, Dietary Fats/adverse effects/analysis/metabolism/*therapeutic use, Plant Components, Aerial, Dietary Fats, Small intestine, Diet, Mice, Inbred C57BL, Endocrinology, White/immunology/metabolism/pathology, Obesity/immunology/metabolism/pathology/*physiopathology, Cattle, Dairy Products, Plant Components
Abstract

Dairy products derived from the milk of cows fed in pastures are characterised by higher amounts of conjugated linoleic acid and α-linolenic acid (ALA), and several studies have shown their ability to reduce cardiovascular risk. However, their specific metabolic effects compared with standard dairy in a high-fat diet (HFD) context remain largely unknown; this is what we determined in the present study with a focus on the metabolic and intestinal parameters. The experimental animals were fed for 12 weeks a HFD containing 20 % fat in the form of a pasture dairy cream (PDC) or a standard dairy cream (SDC). Samples of plasma, liver, white adipose tissue, duodenum, jejunum and colon were analysed. The PDC mice, despite a higher food intake, exhibited lower fat mass, plasma and hepatic TAG concentrations, and inflammation in the adipose tissue than the SDC mice. Furthermore, they exhibited a higher expression of hepaticPPARαmRNA and adipose tissue uncoupling protein 2 mRNA, suggesting an enhanced oxidative activity of the tissues. These results might be explained, in part, by the higher amounts of ALA in the PDC diet and in the liver and adipose tissue of the PDC mice. Moreover, the PDC diet was found to increase the proportions of two strategic cell populations involved in the protective function of the intestinal epithelium, namely Paneth and goblet cells in the small intestine and colon, compared with the SDC diet. In conclusion, a PDC HFD leads to improved metabolic outcomes and to a stronger gut barrier compared with a SDC HFD. This may be due, at least in part, to the protective mechanisms induced by specific lipids.

Published
2014
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17. Insulin resistance is associated with MCP1-mediated macrophage accumulation in skeletal muscle in mice and humans

Author

Amélie Bravard, Jennifer Rieusset, Jingwei-Ji Cao, Etienne Lefai, Hubert Vidal, Annie Durand, David Patsouris, Fabienne Laugerette, Marie-Agnès Chauvin, Martine Laville, Christine Durand, Guillaume Vial, Marie-Caroline Michalski, Cyrille Debard, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Patsouris, David

Subjects
Male, Chemokine, Muscle Physiology, Physiology, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Skeletal/*immunology/metabolism/pathology"*"Myositis/*immunology/metabolism, Mice, Obese, lcsh:Medicine, White adipose tissue, chémokine, Cell Movement, Immune Physiology, lcsh:Science, Immune Response, Chemokine CCL2, Obese"*"Mice, Innate Immune System, Multidisciplinary, biology, Myogenesis, muscle squelettique, medicine.anatomical_structure, Endocrinologie et métabolisme, Tumor necrosis factor alpha, medicine.symptom, Research Article, medicine.medical_specialty, diabète de type 2, Immunology, Inflammation, Mice, Transgenic, macrophage, Cell Line, Insulin resistance, Internal medicine, medicine, Animals, Humans, Transgenic"*"Muscle, Muscle, Skeletal, résistance à l'insuline, Nutrition, Endocrinology and metabolism, Endocrine Physiology, Myositis, Insulin, Macrophages, lcsh:R, Skeletal muscle, Biology and Life Sciences, Animals"*"Cell Line"*"Cell Movement"*"Chemokine CCL2/*physiology"*"Diabetes Mellitus, Nutrients, Type 2/immunology/metabolism"*"Humans"*"Insulin Resistance/*immunology"*"Macrophages/*immunology"*"Male"*"Mice, medicine.disease, Nutritional Diseases, Diet, Mice, Inbred C57BL, Endocrinology, Diabetes Mellitus, Type 2, Immune System, biology.protein, Inbred C57BL"*"Mice, lcsh:Q, Insulin Resistance
Abstract

International audience; Inflammation is now recognized as a major factor contributing to type 2 diabetes (T2D). However, while the mechanisms and consequences associated with white adipose tissue inflammation are well described, very little is known concerning the situation in skeletal muscle. The aim of this study was to investigate, in vitro and in vivo, how skeletal muscle inflammation develops and how in turn it modulates local and systemic insulin sensitivity in different mice models of T2D and in humans, focusing on the role of the chemokine MCP1. Here, we found that skeletal muscle inflammation and macrophage markers are increased and associated with insulin resistance in mice models and humans. In addition, we demonstrated that intra-muscular TNFalpha expression is exclusively restricted to the population of intramuscular leukocytes and that the chemokine MCP1 was associated with skeletal muscle inflammatory markers in these models. Furthermore, we demonstrated that exposure of C2C12 myotubes to palmitate elevated the production of the chemokine MCP1 and that the muscle-specific overexpression of MCP1 in transgenic mice induced the local recruitment of macrophages and altered local insulin sensitivity. Overall our study demonstrates that skeletal muscle inflammation is clearly increased in the context of T2D in each one of the models we investigated, which is likely consecutive to the lipotoxic environment generated by peripheral insulin resistance, further increasing MCP1 expression in muscle. Consequently, our results suggest that MCP1-mediated skeletal muscle macrophages recruitment plays a role in the etiology of T2D.

Published
2014
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19. Low-dose food contaminants trigger sex-specific, hepatic metabolic changes in the progeny of obese mice.: Pollutant mixture and metabolic disorders

Author

Hubert Vidal, Nathalie Vega, Alexandre Le Bourdais, Brigitte Le Magueresse-Battistoni, Michèle Vigier, Emmanuel Labaronne, Danielle Naville, Céline Luquain-Costaz, Claudie Pinteur, Martine Begeot, Yoan Menade, Cyrille Debard, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Institut Multidisciplinaire de Biochimie des Lipides (IMBL), Covalab-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), This work was supported by grants from Institut Benjamin Delessert (2010), Agence Nationale de Sécurité Sanitaire de l'Alimentation, de l'Environnement et du Travail (ANSES, Programme National Environnement-Santé-Travail, EST-2010/2/2007), and The European Foundation of the Study Of Diabetes (EFSD/Novo Nordisk, program 2011). The authors declare no conflicts of interest., Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Male, Tolerable daily intake, Polychlorinated Dibenzodioxins, Mice, Obese, Estrogen receptor, 010501 environmental sciences, 01 natural sciences, Biochemistry, Mice, chemistry.chemical_compound, MESH: Phenols, MESH: Reverse Transcriptase Polymerase Chain Reaction, Ingestion, MESH: Animals, MESH: Mice, Obese, 0303 health sciences, DEHP, Reverse Transcriptase Polymerase Chain Reaction, Polychlorinated Biphenyls, BPA, 3. Good health, Liver, Toxicity, Female, medicine.symptom, Biotechnology, medicine.medical_specialty, medicine.drug_class, Blotting, Western, Biology, Estrogen sulfotransferase, 03 medical and health sciences, Phenols, Persistent Organic Pollutant, MESH: Mice, Inbred C57BL, Internal medicine, Genetics, medicine, MESH: Benzhydryl Compounds, Animals, MESH: Blotting, Western, Estrogen Sulfotransferase, Benzhydryl Compounds, Molecular Biology, MESH: Mice, 030304 developmental biology, 0105 earth and related environmental sciences, Cholesterol, Body Weight, cholesterol, MESH: Male, MESH: Tetrachlorodibenzodioxin, MESH: Body Weight, Mice, Inbred C57BL, MESH: Polychlorinated Biphenyls, Endocrinology, chemistry, 13. Climate action, Estrogen, biosynthesis, Weight gain, MESH: Female, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, MESH: Liver
Abstract

International audience; Environmental contaminants are suspected to be involved in the epidemic incidence of metabolic disorders, food ingestion being a primarily route of exposure. We hypothesized that life-long consumption of a high-fat diet that contains low doses of pollutants will aggravate metabolic disorders induced by obesity itself. Mice were challenged from preconception throughout life with a high-fat diet containing pollutants commonly present in food (2,3,7,8-tetrachlorodibenzo-p-dioxin, polychlorinated biphenyl 153, diethylhexyl phthalate, and bisphenol A), added at low doses in the tolerable daily intake range. We measured several blood parameters, glucose and insulin tolerance, hepatic lipid accumulation, and gene expression in adult mice. Pollutant-exposed mice exhibited significant sex-dependent metabolic disorders in the absence of toxicity and weight gain. In males, pollutants increased the expression of hepatic genes (from 36 to 88%) encoding proteins related to cholesterol biosynthesis and decreased (40%) hepatic total cholesterol levels. In females, there was a marked deterioration of glucose tolerance, which may be related to the 2-fold induction of estrogen sulfotransferase and reduced expression of estrogen receptor α (25%) and estrogen target genes (>34%). Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.

Published
2013
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20. Visceral fat accumulation during lipid overfeeding is related to subcutaneous adipose tissue characteristics in healthy men

Author

Antonio Vidal-Puig, Hubert Vidal, Stéphanie Lambert-Porcheron, Martine Laville, Béatrice Morio, Frank Pilleul, Emmanuelle Meugnier, Maud Alligier, Valérie Sauvinet, Cyrille Debard, Emilie Chanseaume, Laure Gabert, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), RMN et optique : De la mesure au biomarqueur, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Departement d'imagerie Digestive, Hospices Civils de Lyon (HCL), Centre Léon Bérard [Lyon], Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne), Metab Res Labs, Inst Metab Sci, University of Cambridge [UK] (CAM), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Université de Lyon, Centre Hospitalier Universitaire de Lyon, Mécanisme Moléculaire du Diabète (MMD), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Hôpital Edouard Herriot [CHU - HCL], Cambridge Biomedical Research Centre, Partenaires INRAE, Hospices Civils de Lyon (Actions Incitatives), Programme Hospitalier de Recherche Clinique Interregional, Agence Nationale de la Recherche, Medical Research Council Centre for Obesity and Related Metabolic Diseases, National Institute for Health Research, Danone, Ministere de l'Enseignement Superieur et de la Recherche, France, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine Auvergne [CHU Clermont-Ferrand] (CRNH A), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Department of Clinical Biochemistry, Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and ProdInra, Migration

Subjects
Adult, Male, EXPRESSION, medicine.medical_specialty, PROTEINS, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Subcutaneous Fat, Gene Expression, Adipose tissue, 030209 endocrinology & metabolism, Context (language use), White adipose tissue, Intra-Abdominal Fat, Biology, Biochemistry, 03 medical and health sciences, CIDEA, Overnutrition, 0302 clinical medicine, Endocrinology, Internal medicine, medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, METABOLIC SYNDROME, 0303 health sciences, EXPANDABILITY, Biochemistry (medical), HUMANS, Lipid Metabolism, medicine.disease, Obesity, INSULIN, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, OBESITY, Glucose Clamp Technique, Abdomen, Insulin Resistance, Metabolic syndrome, medicine.symptom, Weight gain, Subcutaneous tissue
Abstract

International audience; Context: The hypothesis of a limited expansion of sc adipose tissue during weight gain provides an attractive explanation for the reorientation of excess lipids toward ectopic sites, contributing to visceral adipose depots and metabolic syndrome. Objective: Our objective was to define whether the characteristics of sc adipose tissue influence the partition of lipids toward abdominal fat depots during weight gain in healthy men. Research Design and Methods: Forty-one healthy nonobese volunteers performed a 56-day over-feeding protocol (+760 kcal/d). Insulin sensitivity was estimated by euglycemic hyperinsulinemic clamp. Changes in abdominal visceral and sc adipose tissue depots were measured by magnetic resonance imaging. The fate of ingested lipids before and after overfeeding was investigated using a [d31]palmitate test meal, and gene expression was measured by real-time PCR in sc fat biopsies. Results: Overfeeding led to a 2.5-kg body weight increase with large interindividual variations in abdominal sc and visceral adipose tissues. There was no relationship between the relative expansions of these 2 depots, but the increase in visceral depot was positively associated with the magnitude of the postprandial exogenous fatty acid release in the circulation during the test meal. The regulation of lipid storage-related genes (DGAT2, SREBP1c, and CIDEA) was defective in the sc fat of the subjects exhibiting the largest accumulation in visceral depot. Conclusions: Characteristics of sc adipose tissue appear therefore to contribute to the development of visceral fat depot, supporting the adipose tissue expandability theory and extending it to early stages of weight gain in nonobese subjects. (J Clin Endocrinol Metab 98: 802-810, 2013)

Published
2013
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21. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance

Author

Alessandro Bertuzzi, Serenella Salinari, Hubert Vidal, Geltrude Mingrone, Christine Durand, Paul Zimmet, and Cyrille Debard

Subjects
Anatomy and Physiology, Mouse, medicine.medical_treatment, Glucose uptake, Muscle Fibers, Skeletal, lcsh:Medicine, Type 2 diabetes, insulin signaling pathway, Glycogen Synthase Kinase 3, Mice, Phosphoserine, 0302 clinical medicine, Endocrinology, Insulin Signaling Cascade, Molecular Cell Biology, Medicine, Insulin, Phosphorylation, lcsh:Science, 0303 health sciences, Multidisciplinary, biology, Ribosomal Protein S6 Kinases, 70-kDa, Cell Differentiation, Animal Models, Signaling Cascades, Jejunum, Signal Transduction, Research Article, Adult, medicine.medical_specialty, Proto-Oncogene Proteins c-akt, 030209 endocrinology & metabolism, Endocrine System, Deoxyglucose, insulin resistance, jejunal proteins, Diabetes Mellitus, Experimental, 03 medical and health sciences, Insulin resistance, Model Organisms, In vivo, Internal medicine, Diabetes mellitus, Akt Signaling Cascade, Animals, Humans, Biology, 030304 developmental biology, Diabetic Endocrinology, Glycogen Synthase Kinase 3 beta, Endocrine Physiology, business.industry, lcsh:R, Proteins, medicine.disease, Mice, Inbred C57BL, Insulin receptor, Culture Media, Conditioned, biology.protein, lcsh:Q, Insulin Resistance, business
Abstract

Background Two recent studies demonstrated that bariatric surgery induced remission of type 2 diabetes very soon after surgery and far too early to be attributed to weight loss. In this study, we sought to explore the mechanism/s of this phenomenon by testing the effects of proteins from the duodenum-jejunum conditioned-medium (CM) of db/db or Swiss mice on glucose uptake in vivo in Swiss mice and in vitro in both Swiss mice soleus and L6 cells. We studied the effect of sera and CM proteins from insulin resistant (IR) and insulin-sensitive subjects on insulin signaling in human myoblasts. Methodology/Principal Findings db/db proteins induced massive IR either in vivo or in vitro, while Swiss proteins did not. In L6 cells, only db/db proteins produced a noticeable increase in basal 473Ser-Akt phosphorylation, lack of GSK3β inhibition and a reduced basal 389Thr-p70-S6K1 phosphorylation. Human IR serum markedly increased basal 473Ser-Akt phosphorylation in a dose-dependent manner. Human CM IR proteins increased by about twofold both basal and insulin-stimulated 473Ser-Akt. Basal 9Ser-GSK3β phosphorylation was increased by IR subjects serum with a smaller potentiating effect of insulin. Conclusions These findings show that jejunal proteins either from db/db mice or from insulin resistant subjects impair muscle insulin signaling, thus inducing insulin resistance.

Published
2013

22. n-3 PUFA added to high-fat diets affect differently adiposity and inflammation when carried by phospholipids or triacylglycerols in mice

Author

Alain Géloën, Anne Meynier, Michel Lagarde, Michèle Viau, Lilas Hadji, Michel Guichardant, Manar Awada, Bérengère Benoit, Lucie Ribourg, Christophe O. Soulage, Cyrille Debard, Marie-Caroline Michalski, Claude Genot, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Biopolymères, Interactions Assemblages (BIA), Institut National de la Recherche Agronomique (INRA), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Unité de recherche sur les Biopolymères, Interactions Assemblages (BIA), French National Research Agency (ANR) [ANR-08-ALIA-002], AGECANINOX project, ANR, BMC, Ed., and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_specialty, GPX2, Antioxidant, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], 030309 nutrition & dietetics, medicine.medical_treatment, Endocrinology, Diabetes and Metabolism, Phospholipid, Adipose tissue, Medicine (miscellaneous), lcsh:TX341-641, Clinical nutrition, medicine.disease_cause, Triacylglycerol, n-3 PUFA, 03 medical and health sciences, chemistry.chemical_compound, High-fat diet, Inflammation, Oxidative stress, ACCONNECTING PHOSPHOLIPIDS, DOCOSAHEXAENOIC ACID, GLUTATHIONE-PEROXIDASE, OXIDATION-PRODUCTS, INSULIN-RESISTANCE, DEFICIENT MICE, KRILL OIL, TISSUE, DISEASE, SUPPLEMENTATION, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], lcsh:RC620-627, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, Nutrition and Dietetics, business.industry, Research, Leptin, 3. Good health, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, lcsh:Nutritional diseases. Deficiency diseases, Endocrinology, Biochemistry, chemistry, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, lcsh:Nutrition. Foods and food supply, Polyunsaturated fatty acid
Abstract

Background Dietary intake of n-3 polyunsaturated fatty acids (PUFA) is primarily recognized to protect against cardiovascular diseases, cognitive dysfunctions and the onset of obesity and associated metabolic disorders. However, some of their properties such as bioavailability can depend on their chemical carriers. The objective of our study was to test the hypothesis that the nature of n-3 PUFA carrier results in different metabolic effects related to adiposity, oxidative stress and inflammation. Methods 4 groups of C57BL/6 mice were fed for 8 weeks low fat (LF) diet or high-fat (HF, 20%) diets. Two groups of high-fat diets were supplemented with long-chain n-3 PUFA either incorporated in the form of phospholipids (HF-ω3PL) or triacylglycerols (HF-ω3TG). Results Both HF-ω3PL and HF-ω3TG diets reduced the plasma concentrations of (i) inflammatory markers such as monocyte chemoattractant protein-1 (MCP-1) and interleukin 6 (IL-6), (ii) leptin and (iii) 4-hydroxy-2-nonenal (4-HNE), a marker of n-6 PUFA-derived oxidative stress compared with the control HF diet. Moreover, in both HF-ω3PL and HF-ω3TG groups, MCP-1 and IL-6 gene expressions were decreased in epididymal adipose tissue and the mRNA level of gastrointestinal glutathione peroxidase GPx2, an antioxidant enzyme, was decreased in the jejunum compared with the control HF diet. The type of n-3 PUFA carrier affected other outcomes. The phospholipid form of n-3 PUFA increased the level of tocopherols in epididymal adipose tissue compared with HF-ω3TG and resulted in smaller adipocytes than the two others HF groups. Adipocytes in the HF-ω3PL and LF groups were similar in size distribution. Conclusion Supplementation of mice diet with long-chain n-3 PUFA during long-term consumption of high-fat diets had the same lowering effects on inflammation regardless of triacyglycerol or phospholipid carrier, whereas the location of these fatty acids on a PL carrier had a major effect on decreasing the size of adipocytes that was not observed with the triacyglycerol carrier. Altogether, these results would support the development functional foods containing LC n-3 PUFA in the form of PL in order to prevent some deleterious outcomes associated with the development of obesity.

Published
2013
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23. High-fat diet action on adiposity, inflammation, and insulin sensitivity depends on the control low-fat diet

Author

Manar Awada, Frédéric Capel, Alain Géloën, Pascale Plaisancié, Hubert Vidal, Jennifer Rieusset, Monique Estienne, Corinne Malpuech-Brugère, Bérengère Benoit, Sandra Pesenti, Cyrille Debard, Béatrice Morio, Marie-Caroline Michalski, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, CNIEL (Centre National Interprofessionnel de l'Economie Laitiere), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), and Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA)

Subjects
Male, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Biomedical Research, AUC, Endocrinology, Diabetes and Metabolism, LFD, Adipose tissue, White adipose tissue, Weight Gain, eWAT, chemistry.chemical_compound, Mice, 0302 clinical medicine, Endocrinology, chow LFD, Brown adipose tissue, subcutaneous white adipose tissue, Diet, Fat-Restricted, triglycerides, Adiposity, 2. Zero hunger, 0303 health sciences, Nutrition and Dietetics, messenger RNA, High fat diet, rWAT, Area under the curve, food and beverages, epididymal white adipose tissue, Insulin sensitivity, retroperitoneal white adipose tissue, 3. Good health, medicine.anatomical_structure, high-fat diet, Liver, TG, Animal studies, medicine.symptom, sy-HFD, sy-LFD, medicine.medical_specialty, area under the curve, WAT, mRNA, pAKT, Subcutaneous Fat, interleukin 6, 030209 endocrinology & metabolism, Inflammation, phosphorylated AKT, Biology, Diet, High-Fat, low-fat diet, 03 medical and health sciences, semisynthetic low-fat diet, white adipose tissue, Internal medicine, medicine, Animals, cluster of differentiation 68, CD68, 030304 developmental biology, scWAT, IL-6, Cholesterol, CD11c, Macrophages, BAT, brown adipose tissue, monocyte chemoattractant protein 1, Lipid Metabolism, Dietary Fats, Mice, Inbred C57BL, cluster of differentiation 11c, chemistry, semisynthetic high-fat diet, MCP1, HFD, Insulin Resistance, Energy Intake, ch-LFD
Abstract

Animal studies using a high-fat diet (HFD) have studied the effects of lipid overconsumption by comparing a defined HFD either with a natural-ingredient chow diet or with a defined low-fat diet (LFD), despite the dramatic differences between these control diets. We hypothesized that these differences in the control diet could modify the conclusions regarding the effects that an increase of fat in the diet has on several metabolic parameters. For 11 weeks, C57bl6/J mice were fed a low-fat chow diet (8% energy from fat), a typical semisynthetic LFD (12%), or a semisynthetic HFD (sy-HF) (40%). Conclusions about the effect of sy-HF on body weight gain, subcutaneous adipose tissue, insulin sensitivity, and adipose tissue inflammation were modified according to the control LFD. Conversely, conclusions about epididymal and retroperitoneal adipose tissue; fat intake effects on liver and muscular lipids, cholesterol, free fatty acids, and markers of low-grade inflammation; and of adipose tissue macrophage infiltration were the same regardless of the use of low-fat chow diet or semisynthetic LFD. For some physiological outcomes, conflicting conclusions were even reached about the effects of increased fat intake according to the chosen low-fat control. Some deleterious effects of sy-HF may not be explained by lipid overconsumption but rather by the overall quality of ingredients in a semisynthetic diet. According to the control LFD chosen, conclusions on the lipid-related effects of HFDs must be formulated with great care because some end points are profoundly affected by the ingredient composition of the diet rather than by fat content.

Published
2013
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24. Insulin-sensitizing effects on muscle and adipose tissue after dietary fiber intake in men and women with metabolic syndrome

Author

Cyrille Debard, Hubert Vidal, Fariba Shojaee-Moradie, John Wright, M. Denise Robertson, David Russell-Jones, Emmanuelle Loizon, and A. Margot Umpleby

Subjects
Adult, Dietary Fiber, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Biopsy, Clinical Biochemistry, Gene Expression, Context (language use), Real-Time Polymerase Chain Reaction, Biochemistry, Zea mays, law.invention, Membrane Potentials, Endocrinology, Insulin resistance, Randomized controlled trial, law, Internal medicine, Diabetes mellitus, medicine, Humans, Single-Blind Method, RNA, Messenger, Aged, Metabolic Syndrome, business.industry, Insulin, Muscles, Biochemistry (medical), Type 2 Diabetes Mellitus, Glucose clamp technique, Middle Aged, medicine.disease, Lipid Metabolism, Diet, Glucose, Adipose Tissue, Liver, Glucose Clamp Technique, Cytokines, Female, Metabolic syndrome, Insulin Resistance, business, Biomarkers
Abstract

Context: Dietary fibers have been associated with a reduced incidence of type 2 diabetes mellitus in epidemiological studies; however, the precise mechanisms are unknown. Objective: The objective of the study was to evaluate the efficacy and site of action of an insoluble dietary fiber derived from maize (HAM-RS2) in improving insulin resistance in subjects at increased risk of type 2 diabetes mellitus. Design: This study was a randomized, controlled crossover, dietary intervention study. Setting: The study was conducted at the Centre for Diabetes, Endocrinology, and Research, Royal Surrey County Hospital, Guildford, United Kingdom. Participants: Fifteen men and women with insulin resistance participated in the study. Intervention: The intervention included 40 g/d HAM-RS2 compared with a matched placebo for 8 wk. Main Outcome Measures: After each supplement, participants underwent a two-step hyperinsulinemic-euglycemic clamp study with the addition of glucose tracers; a meal tolerance test; arteriovenous sampling across forearm muscle tissue; and a sc adipose tissue biopsy for assessment of gene expression. Results: There was enhanced uptake of glucose into the forearm muscle measured by arteriovenous sampling (65 ± 15% increase after resistant starch; P < 0.001). Adipose tissue function was also affected, with enhanced fatty acid suppression after HAM-RS2 treatment and an increase in gene expression for hormone sensitive lipase (P = 0.005), perilipin (P = 0.011), lipoprotein lipase (P = 0.014), and adipose triglyceride lipase (P = 0.03) in biopsy samples. There was no effect on the insulin sensitivity of hepatic glucose production or plasma lipids after HAM-RS2. Conclusion: HAM-RS2 improved peripheral but not hepatic insulin resistance and requires further study as an intervention in patients with or at risk for type 2 diabetes.

Published
2012

25. Subcutaneous Adipose Tissue Remodeling during the Initial Phase of Weight Gain Induced by Overfeeding in Humans

Author

J. Brozek, Béatrice Morio, Emmanuelle Meugnier, Maud Alligier, Stéphanie Lambert-Porcheron, J.Y. Scoazec, Emmanuelle Loizon, Monique Sothier, Martine Laville, Cyrille Debard, Ali Ait Hssain, Emilie Chanseaume, Hubert Vidal, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RH), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), ProdInra, Migration, Université de Lyon, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre Hospitalier Universitaire de Lyon, Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand, Genfit, Hospices Civils de Lyon (Actions incitatives), Program Hospitalier de Recherche Clinique interregional, Agence Nationale de la Recherche, ISI of Agence pour l'Innovation OSEO (IT-DIAB), Danone, Ministere de l'Enseignement Superieur et de la Recherche, France, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble

Subjects
Male, Time Factors, Angiogenesis, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Adipose tissue, White adipose tissue, Weight Gain, Biochemistry, ANGIOGENESIS, Extracellular matrix, Eating, 0302 clinical medicine, Endocrinology, Overnutrition, ComputingMilieux_MISCELLANEOUS, Adiposity, GENE-EXPRESSION, 0303 health sciences, INSULIN-RESISTANCE, Middle Aged, 3. Good health, [SDV] Life Sciences [q-bio], PROBE LEVEL, SKELETAL-MUSCLE, medicine.symptom, OBESE SUBJECTS, Signal Transduction, Adult, medicine.medical_specialty, Adolescent, 030209 endocrinology & metabolism, Context (language use), Biology, METABOLISM, 03 medical and health sciences, Young Adult, Internal medicine, medicine, EXTRACELLULAR-MATRIX, Humans, 030304 developmental biology, Gene Expression Profiling, Biochemistry (medical), Editorials, Lipid metabolism, medicine.disease, Microarray Analysis, Subcutaneous Fat, Abdominal, ADIPOGENESIS, FAT, Weight gain
Abstract

International audience; Context: Deciphering the early processes occurring in adipose tissue during weight gain is a major issue for understanding the development of fat mass and obesity. Experimental overfeeding in humans is a unique situation to tackle these events. Objective: Our aim was to identify the pathways involved in sc adipose tissue remodeling during the initial phase of weight gain. Research Design and Methods: Forty-four healthy men were involved in an overfeeding protocol with a lipid-enriched diet (+ 760 kcal/d) for 2 months. Subcutaneous abdominal adipose tissue biopsies were taken for histology, transcriptomics, and Western blotting in the basal state, after 14 d, and at the end of the protocol. Results: Overfeeding significantly increased body weight (+ 2.5 kg) and fat mass. Reorganization of gene expression patterns occurred in adipose tissue with an up-regulation of numerous genes involved in lipid metabolism and storage, followed by clusters of genes related to angiogenesis and extracellular matrix remodeling. Histological examination showed increased microvascular density and connective tissue deposition after 56 d of overfeeding, with no changes in the number of macrophages or inflammatory cells. Inhibition of the canonical Wnt/beta-catenin signaling pathway and induction of the renin-angiotensin system might be implicated in the remodeling of sc adipose tissue. Conclusions: We characterize the coordinated and time-dependent processes that occur in human adipose tissue during the early phase of weight gain in healthy subjects and identify pathways representing potential targets in pathologies of adipose development, including obesity. (J Clin Endocrinol Metab 97: E183-E192, 2012)

Published
2012
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26. Genetic association and gene expression analysis identify FGFR1 as a new susceptibility gene for human obesity

Author

Anne Bouloumié, Karine Clément, Hong Jiao, Dominique Langin, Mikael Rydén, Anders Hamsten, Pilar Galan, Magdalena Taube, Ingrid Dahlman, Anna Benrick, Cyrille Debard, Chantal Simon, Martine Laville, John-Olov Jansson, Angela Silveira, Caroline Hansson, Corneliu Henegar, Tomas Axelsson, Peter Arner, Juha Kere, Hubert Vidal, Karin Dahlman-Wright, Anke Hinney, Niklas Mejhert, Suzanne L. Dickson, Department of Biosciences and Nutrition, Karolinska Institutet [Stockholm], Clinical Research Centre, Karolinska University Hospital [Stockholm], Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-University of Gothenburg ( GU ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Atherosclerosis Research Unit, Karolinska Institutet [Stockholm]-Department of Medicine Solna-Cardiovascular Genetics Group, Unité de Recherche en Epidémiologie Nutritionnelle ( UREN ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire d'épidémiologie et de santé publique, Université Louis Pasteur - Strasbourg I, Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of medical sciences, Uppsala University-Molecular Medicine-Science for Life Laboratory, Department of child and adolescent psychiatry, Universität Duisburg-Essen [Essen], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg]-University of Gothenburg (GU), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche en Epidémiologie Nutritionnelle (UREN), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Sahlgrenska Academy at University of Gothenburg [Göteborg], Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Department of Biosciences and Nutrition [Karolinska Insitutet, Sueden] (BioNut), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Sorbonne Paris Cité (USPC)-Université Paris 13 (UP13)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Science for Life Laboratory [Solna], Royal Institute of Technology [Stockholm] (KTH ), AFA Insurance, Swedish Heart and Lung Foundation, Swedish Research Council [8691], Novo Nordic Foundation, Swedish Diabetes Association, Knut and Alice Wallenberg Foundation, Stockholm County Council [562183], European Commission [LSHM-CT-2005-018734, ADAPT FP7-Health-2007-A], Direction de la Recherche Clinique/Assistance Publique-Hopitaux de Paris, Programmes Hospitaliers de Recherche Clinique [AOR 02076], Le site de l'Association de Langue Francaise pour l'Etude du Diabete et des Maladies Metaboliques, region Ile de France, Swedish Medical Research Council [VR k2007-54x-20328-013], European Union [FP7-HEALTH-2009-241592, FP7-KBBE-2009-3-245009], ALF Goteborg [SU7601], Swedish Foundation for Strategic Research [A305-188], German Ministry of Education and Research (NGFNplus) [01GS0820], Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Sorbonne Paris Nord, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universität Duisburg-Essen = University of Duisburg-Essen [Essen]

Subjects
Male, Fibroblast Growth Factor, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Messenger, Medizin, Adipose tissue, Appetite, Biochemistry, Rats, Sprague-Dawley, 0302 clinical medicine, Endocrinology, Odds Ratio, Child, media_common, 2. Zero hunger, 0303 health sciences, education.field_of_study, Blotting, Reverse Transcriptase Polymerase Chain Reaction, Skeletal, Single Nucleotide, Adipose Tissue, Muscle, Female, Western, Type 1, Receptor, Adult, medicine.medical_specialty, Adolescent, Animals, Chi-Square Distribution, European Continental Ancestry Group, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Hypothalamus, Obesity, Polymorphism, RNA, Rats, Sprague-Dawley, media_common.quotation_subject, Population, Blotting, Western, 030209 endocrinology & metabolism, Single-nucleotide polymorphism, Context (language use), Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Receptor, Fibroblast Growth Factor, Type 1, education, Muscle, Skeletal, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, business.industry, Biochemistry (medical), Odds ratio, Fat cell differentiation, medicine.disease, stomatognathic diseases, business
Abstract

International audience; CONTEXT: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. OBJECTIVE: Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. DESIGN: The study was designed to genotype common FGFR1 single-nucleotide polymorphisms (SNP) in large cohorts, confirm significant results in additional cohorts, and measure FGFR1 expression in human adipose tissue and in rodent hypothalamus. SETTING: General community and referral centers for specialized care was the setting for the study. PARTICIPANTS: We genotyped FGFR1 SNP in 2438 obese and 2115 lean adults and 985 obese and 532 population-based children. Results were confirmed in 928 obese and 2738 population-based adults and 487 obese and 441 lean children. Abdominal sc adipose tissue was investigated in 202 subjects. We also investigated diet-induced, obese fasting, and fed rats. MAIN OUTCOME MEASURES: We analyzed the association between FGFR1 SNP and obesity. In secondary analyses, we related adipose FGFR1 expression to genotype, obesity, and degree of fat cell differentiation and related hypothalamic FGFR1 to energy balance. RESULTS: FGFR1 rs7012413*T was nominally associated with obesity in all four cohorts; metaanalysis odds ratio = 1.17 (95% confidence interval = 1.10-1.25), and P = 1.8 × 10(-6), which was P = 7.0 × 10(-8) in the recessive model. rs7012413*T was associated with FGFR1 expression in adipose tissue (P < 0.0001). In this organ, but not in skeletal muscle, FGFR1 mRNA (P < 0.0001) and protein (P < 0.05) were increased in obesity. In rats, hypothalamic expression of FGFR1 declined after fasting (P < ]0.001) and increased after diet-induced obesity (P < 0.05). CONCLUSIONS: FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.

Published
2011
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27. GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia

Author

Cyrille Debard, Philippe Moulin, Micheline Merlin, Noël Peretti, Etienne Lefai, Sophie Bernard, C. Marcais, Sybil Charrière, Agnès Sassolas, Mathilde Di Filippo, Mireille Delay, Alain Lachaux, Institut National de la Recherche Agronomique (INRA), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Mécanisme Moléculaire du Diabète (MMD), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Montréal - Hôpital Hôtel-Dieu, Partenaires INRAE, Centre de Biologie et de pathologie Est, Institut National de la Sante et de la Recherche Medicale, and French Society of Nutrition

Subjects
Proband, Adult, Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Mutation, Missense, CHO Cells, 030204 cardiovascular system & hematology, Biology, Biochemistry, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Cricetulus, Cricetinae, Genotype, Chylomicrons, Missense mutation, Animals, Humans, Allele, Apolipoproteins A, 030304 developmental biology, Receptors, Lipoprotein, Genetics, 0303 health sciences, Lipoprotein lipase, Biochemistry (medical), Haplotype, GPIHBP1, Infant, DNA, Molecular biology, Pedigree, Lipoprotein Lipase, Liver, Pancreatitis, Apolipoprotein A-V, Mutation, Apolipoprotein C-II, Hyperlipoproteinemia Type I, Carrier Proteins, Lipoprotein
Abstract

Context: GPIHBP1 is a new endothelial binding site for lipoprotein lipase (LPL), the key enzyme for intravascular lipolysis of triglyceride-rich lipoproteins (TGRL). We have identified two new missense mutations of the GPIHBP1 gene, C89F and G175R, by systematic sequencing in a cohort of 376 hyperchylomicronemic patients without mutations on the LPL, APOC2, or APOA5 gene. Objective: Phenotypic expression and functional consequences of these two mutations were studied. Design: We performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells. Results: Probands are an adult with a homozygous G175R mutation and a child with a hemizygous C89F neomutation and a deletion of the second allele. C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype. Both patients had resistant hyperchylomicronemia, low LPL activity, and history of acute pancreatitis. In CHO pgsA-745 cells, both G175R and C14F variants reduce the expression of GPIHBP1 at the cell surface. C89F mutation is responsible for a drastic LPL-binding defect to GPIHBP1. C14F may further potentiate C89F effect. Conclusions: The emergence of hyperchylomicronemia in the generation after a neomutation further establishes a critical role for GPIHBP1 in TGRL physiopathology in humans. Our results highlight the crucial role of C65-C89 disulfide bond in LPL binding by GPIHBP1 Ly6 domain. Furthermore, we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting.

Published
2011
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28. Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans

Author

Philippe Valet, Jennifer Jager, Estelle Wanecq, Hubert Vidal, Cyrille Debard, Frédéric Bost, Camille Attané, Cédric Dray, Isabelle Castan-Laurell, Emmanuel Disse, Charlotte Guigné, Danièle Daviaud, Jean-François Tanti, Pascal G.P. Martin, Martine Laville, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre méditérannéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Pharmacologie et Toxicologie, Institut National de la Recherche Agronomique (INRA), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Claude Bernard Lyon 1 (UCBL), and Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)

Subjects
Leptin, Male, Physiology, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Messenger, Adipose tissue, Inbred C57BL, Receptors, G-Protein-Coupled, Mice, 0302 clinical medicine, Receptors, Insulin, Glucose homeostasis, Apelin Receptors, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, Skeletal, Middle Aged, Glucose clamp technique, Apelin, medicine.anatomical_structure, Adipose Tissue, Intercellular Signaling Peptides and Proteins, Muscle, Female, Type 2, Adult, medicine.medical_specialty, 030209 endocrinology & metabolism, Biology, G-Protein-Coupled, 03 medical and health sciences, Insulin resistance, Adipokines, Physiology (medical), Internal medicine, Diabetes Mellitus, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Muscle, Skeletal, 030304 developmental biology, Apelin receptor, Skeletal muscle, medicine.disease, Mice, Inbred C57BL, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Carrier Proteins, Glucose Clamp Technique, Insulin Resistance, RNA
Abstract

International audience; Apelin, an adipocyte-secreted factor upregulated by insulin, is increased in adipose tissue (AT) and plasma with obesity. Apelin was recently identified as a new player in the control of glucose homeostasis. However, the regulation of apelin and APJ (apelin receptor) expression in skeletal muscle in relation to insulin resistance or type 2 diabetes is not known. Thus we studied apelin and APJ expression in AT and muscle in different mice models of obesity and in type 2 diabetic patients. In insulin-resistant high-fat (HF)-fed mice, apelin and APJ expression were increased in AT compared with control. This was not the case in AT of highly insulin-resistant db/db mice. In skeletal muscle, apelin expression was similar in control and HF-fed mice and decreased in db/db mice. APJ expression was decreased in both HF-fed and db/db mice. Control subjects and type 2 diabetic patients were subjected to a hyperinsulinemic-euglycemic clamp, and tissues biopsies were obtained before and at the end of the clamp. There was no significant difference in basal apelin and APJ expression in AT and muscle between control and diabetic patients. However, apelin plasma levels were significantly increased in diabetic patients. During the clamp, hyperinsulinemia increased apelin and APJ expression in AT of control but not in diabetic subjects. In muscle, only APJ mRNA levels were increased in control but also in diabetic patients. Taken together, these data show that apelin and APJ expression in mice and humans is regulated in a tissue-dependent manner and according to the severity of insulin resistance.

Published
2010
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29. Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake

Author

Adriana Márquez-Quiñones, Dominique Langin, Karine Clément, Wim H. M. Saris, Teodora Handjieva-Darlenska, Marion Combes, Ping Wang, Andreas Pfeiffer, Dimitris K. Babalis, David M. Mutch, Thomas Meinert Larsen, Susan A. Jebb, Claus Holst, Edwin C. M. Mariman, Hubert Vidal, Arne Astrup, Nathalie Viguerie, Pavla Kalouskova, Balbine Roussel, Cyrille Debard, J. Alfredo Martínez, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Santé Publique et Informatique Médicale (SPIM), Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Human Health and Nutritional Sciences, University of Guelph, Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Department of Human Biology, Maastricht University [Maastricht], Institute of Preventive Medicine, Copenhagen University Hospitals, Department of Physiology and Nutrition, Universidad de Navarra [Pamplona] (UNAV), Department of Pharmacology and Toxicology, Medical Faculty, Medical University, Obesity Management Centre, Institute of Endocrinology, Human Nutrition Research, Elsie Widdowson Laboratory, Department of Internal Medicine, University Hospital of Heraklion, Department of Clinical Nutrition, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Human Nutrition, Faculty of Life Science [Copenhagen], University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Centre de Recherche en Nutrition Humaine d'Ile-de-France (CRNH-IDF), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], European Community [FP6-513946], Institut National de la Sante et de la Recherche Medicale, Region Midi-Pyrenees, Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Université Paris 13 (UP13)-Institut National de la Recherche Agronomique (INRA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Institut National Agronomique Paris-Grignon (INA P-G)-CETAF-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine moléculaire de Rangueil ( I2MR ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Santé Publique et Informatique Médicale ( SPIM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Régulations métaboliques, nutrition et diabètes - UM55 ( RMND UM55 ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon ( INSA Lyon ), Université de Lyon-Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Hospices Civils de Lyon ( HCL ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), Universidad de Navarra [Pamplona] ( UNAV ), Charité Universitäts Medizin Berlin, University of Copenhagen ( KU ), Centre de Recherche en Nutrition Humaine d'Ile-de-France ( CRNH-IDF ), Université Paris 13 ( UP13 ) -Institut National de la Recherche Agronomique ( INRA ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut de Veille Sanitaire (INVS)-Assistance publique - Hôpitaux de Paris (AP-HP)-Conservatoire National des Arts et Métiers [CNAM] ( CNAM ) -Institut National Agronomique Paris-Grignon ( INA P-G ) -CETAF-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Paris 13 (UP13)-CETAF-Institut National Agronomique Paris-Grignon (INA P-G)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut de Veille Sanitaire (INVS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humane Biologie, RS: NUTRIM - R4 - Gene-environment interaction, and RS: NUTRIM - R1 - Metabolic Syndrome

Subjects
MESH: Treatment Failure, Blood Pressure, MESH: Energy Intake, Transcriptome, 0302 clinical medicine, HIGH-PROTEIN, Models, MESH: Models, Genetic, GENE-EXPRESSION, Oligonucleotide Array Sequence Analysis, MESH: Treatment Outcome, 0303 health sciences, MACRONUTRIENT, Reducing, MESH : Reverse Transcriptase Polymerase Chain Reaction, MESH: Blood Pressure, MESH: Follow-Up Studies, LOW-FAT, Gene expression profiling, 3. Good health, MESH : Oligonucleotide Array Sequence Analysis, Adipose Tissue, MESH: Adipose Tissue, medicine.medical_specialty, Diet, Reducing, LOSS MAINTENANCE, MESH : Adipose Tissue, 03 medical and health sciences, MESH: Gene Expression Profiling, MESH: Weight Loss, MESH : Treatment Failure, Genetic, Humans, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Humans, MESH : Gene Expression Profiling, MESH : Humans, MESH : Follow-Up Studies, MESH: Adult, Anthropometry, medicine.disease, Obesity, Endocrinology, MICROARRAY DATA, Energy intake, MESH: Female, Calorie, Time Factors, Medicine (miscellaneous), Adipose tissue, MESH : Models, Genetic, HUMAN OBESITY, Weight loss, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH : RNA, MESH: Obesity, MESH : Female, Treatment Failure, MESH : Diet, Reducing, 2. Zero hunger, MESH: Diet, Reducing, Nutrition and Dietetics, Reverse Transcriptase Polymerase Chain Reaction, MESH : Adult, ADIPOCYTES, Glycemic index, Treatment Outcome, MESH : Obesity, Female, medicine.symptom, Dieting, MESH : Time Factors, Adult, 030209 endocrinology & metabolism, MESH : Treatment Outcome, Biology, DiOGenes, MESH: RNA, Internal medicine, Weight Loss, medicine, MESH : Blood Pressure, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, LOSS DIETS, Models, Genetic, Gene Expression Profiling, MESH: Time Factors, MESH : Energy Intake, Diet, MESH: Oligonucleotide Array Sequence Analysis, GLYCEMIC INDEX, RNA, MESH : Weight Loss, Energy Intake, Follow-Up Studies
Abstract

Background: The mechanisms underlying body weight evolution after diet-induced weight loss are poorly understood. Objective: We aimed to identify and characterize differences in the subcutaneous adipose tissue (SAT) transcriptome of subjects with different weight changes after energy restriction-induced weight loss during 6 mo on 4 different diets. Design: After an 8-wk low-calorie diet (800 kcal/d), we randomly assigned weight-reduced obese subjects from 8 European countries to receive 4 diets that differed in protein and glycemic index content. In addition to anthropometric and plasma markers, SAT biopsies were taken at the beginning [clinical investigation day (CID) 2] and end (CID3) of the weight follow-up period. Microarray analysis was used to define SAT gene expression profiles at CID2 and CID3 in 22 women with continued weight loss (successful group) and in 22 women with weight regain (unsuccessful group) across the 4 dietary arms. Results: Differences in SAT gene expression patterns between successful and unsuccessful groups were mainly due to weight variations rather than to differences in dietary macronutrient content. An analysis of covariance with total energy intake as a covariate identified 1338 differentially expressed genes. Cellular growth and proliferation, cell death, cellular function, and maintenance were the main biological processes represented in SAT from subjects who regained weight. Mitochondrial oxidative phosphorylation was the major pattern associated with continued weight loss. Conclusions: The ability to control body weight loss independent of energy intake or diet composition is reflected in the SAT transcriptome. Although cell proliferation may be detrimental, a greater mitochondrial energy gene expression is suggested as being beneficial for weight control. This trial was registered at clinicaltrials.gov as NCT00390637. © 2010 American Society for Nutrition.

Published
2010
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30. High protein intake reduces intrahepatocellular lipid deposition in humans

Author

Kim Anne Lê, Peter Vermathen, Luc Tappy, Philippe Schneiter, Nathalie Stefanoni, Hubert Vidal, Bertrand Cariou, David Faeh, Roland Kreis, Michael Ith, Chris Boesch, Maud Chétiveaux, Murielle Bortolotti, Michel Krempf, and Cyrille Debard

Subjects
Adult, Leptin, Male, medicine.medical_specialty, medicine.drug_class, medicine.medical_treatment, Medicine (miscellaneous), Adipose tissue, Biology, Fatty Acids, Nonesterified, Bile Acids and Salts, Young Adult, Insulin resistance, Weight loss, Internal medicine, medicine, Glucose homeostasis, Humans, Exertion, Nutrition and Dietetics, Cross-Over Studies, Bile acid, 3-Hydroxybutyric Acid, Insulin, Metabolism, medicine.disease, Lipid Metabolism, Dietary Fats, Endocrinology, Liver, Tissue Plasminogen Activator, Dietary Proteins, medicine.symptom, Insulin Resistance, Energy Intake, Sterol Regulatory Element Binding Protein 1
Abstract

BACKGROUND: High sugar and fat intakes are known to increase intrahepatocellular lipids (IHCLs) and to cause insulin resistance. High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients, but its effects on IHCLs remain unknown. OBJECTIVE: The aim was to assess the effect of high protein intake on high-fat diet-induced IHCL accumulation and insulin sensitivity in healthy young men. DESIGN: Ten volunteers were studied in a crossover design after 4 d of either a hypercaloric high-fat (HF) diet; a hypercaloric high-fat, high-protein (HFHP) diet; or a control, isocaloric (control) diet. IHCLs were measured by (1)H-magnetic resonance spectroscopy, fasting metabolism was measured by indirect calorimetry, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and plasma concentrations were measured by enzyme-linked immunosorbent assay and gas chromatography-mass spectrometry; expression of key lipogenic genes was assessed in subcutaneous adipose tissue biopsy specimens. RESULTS: The HF diet increased IHCLs by 90 +/- 26% and plasma tissue-type plasminogen activator inhibitor-1 (tPAI-1) by 54 +/- 11% (P < 0.02 for both) and inhibited plasma free fatty acids by 26 +/- 11% and beta-hydroxybutyrate by 61 +/- 27% (P < 0.05 for both). The HFHP diet blunted the increase in IHCLs and normalized plasma beta-hydroxybutyrate and tPAI-1 concentrations. Insulin sensitivity was not altered, whereas the expression of sterol regulatory element-binding protein-1c and key lipogenic genes increased with the HF and HFHP diets (P < 0.02). Bile acid concentrations remained unchanged after the HF diet but increased by 50 +/- 24% after the HFHP diet (P = 0.14). CONCLUSIONS: Protein intake significantly blunts the effects of an HF diet on IHCLs and tPAI-1 through effects presumably exerted at the level of the liver. Protein-induced increases in bile acid concentrations may be involved. This trial was registered at www.clinicaltrials.gov as NCT00523562.

Published
2009

31. Effects of docosahexaenoic acid on some megakaryocytic cell gene expression of some enzymes controlling prostanoid synthesis

Author

Nicolas Guillot, Michel Lagarde, Hubert Vidal, Evelyne Véricel, Catherine Calzada, Cyrille Debard, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Régulations métaboliques, nutrition et diabètes - UM55 (RMND UM55), Université Claude Bernard Lyon 1 (UCBL), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Vericel, Evelyne, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)

Subjects
MESH: Oxidation-Reduction, Antioxidant, antioxidant, genetic structures, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Peroxisome proliferator-activated receptor, 030204 cardiovascular system & hematology, medicine.disease_cause, Biochemistry, Lipid peroxidation, megakaryocyte, chemistry.chemical_compound, Glutathione Peroxidase GPX1, 0302 clinical medicine, Malondialdehyde, oxidative stress, PPAR delta, glutathione peroxidase, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 0303 health sciences, Arachidonic Acid, Glutathione peroxidase, Fatty Acids, catalase, food and beverages, docosahexaenoic acid, 3. Good health, MESH: Fatty Acids, MESH: Megakaryocytes, MESH: Docosahexaenoic Acids, Docosahexaenoic acid, lipids (amino acids, peptides, and proteins), Megakaryocytes, Oxidation-Reduction, medicine.medical_specialty, MESH: PPAR-beta, MESH: Gene Expression, Docosahexaenoic Acids, MESH: Malondialdehyde, MESH: Prostaglandin-Endoperoxide Synthases, Biophysics, Biology, Cell Line, 03 medical and health sciences, Internal medicine, medicine, Humans, MESH: PPAR delta, PPAR-beta, Molecular Biology, phospholipids, 030304 developmental biology, MESH: Phospholipids, MESH: Humans, thromboxane synthase, Cell Biology, Glutathione, MESH: Arachidonic Acid, MESH: Cell Line, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, chemistry, Prostaglandin-Endoperoxide Synthases, MESH: Prostaglandins, MESH: Glutathione Peroxidase, Prostaglandins, biology.protein, gene expression, Thromboxane-A synthase, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, Oxidative stress
Abstract

International audience; Beneficial effects of docosahexaenoic acid (DHA) intake in the prevention of cardiovascular diseases are known, and platelets play a crucial role in cardiovascular complications. However, high doses of DHA may increase lipid peroxidation and induce deleterious effects, notably in platelets. This led us to investigate the effect of DHA on gene expression of some enzymes controlling redox status and prostanoid formation in human megakaryoblastic cells (MEG-01 cell line). MEG-01 cells were incubated in presence of DHA (10 and 100 micromol/L) for 6h. DHA enrichment up-regulated glutathione peroxidase-1 and thromboxane synthase mRNA. DHA increased gene catalase expression and up-regulated PPAR beta/delta and PPAR gamma mRNA in presence of high concentration of DHA. In conclusion, our results support an antioxidant mechanism of DHA. The effects of DHA on cellular redox status could, with others, provide an explanation for the beneficial influence of low consumption of DHA on cardiovascular events.

Published
2008
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32. Effects of four-week high-fructose diet on gene expression in skeletal muscle of healthy men

Author

Luc Tappy, Hubert Vidal, Rodrigue Stettler, Kim-Anne Lê, Eric Ravussin, Emmanuelle Loizon, David Faeh, Chris Boesch, Cyrille Debard, University of Zurich, and Tappy, L

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, 610 Medicine & health, Fructose, Carbohydrate metabolism, Biology, White People, chemistry.chemical_compound, Endocrinology, Insulin resistance, Reference Values, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Dietary Carbohydrates, Humans, Intramyocellular lipids, Muscle, Skeletal, Skeletal muscle, 10060 Epidemiology, Biostatistics and Prevention Institute (EBPI), General Medicine, medicine.disease, Obesity, 1310 Endocrinology, 2712 Endocrinology, Diabetes and Metabolism, medicine.anatomical_structure, chemistry, Gene Expression Regulation, 2724 Internal Medicine, Energy Metabolism, Homeostasis
Abstract

AIMS: A high-fructose diet (HFrD) may play a role in the obesity and metabolic disorders epidemic. In rodents, HFrD leads to insulin resistance and ectopic lipid deposition. In healthy humans, a four-week HFrD alters lipid homoeostasis, but does not affect insulin sensitivity or intramyocellular lipids (IMCL). The aim of this study was to investigate whether fructose may induce early molecular changes in skeletal muscle prior to the development of whole-body insulin resistance. METHODS: Muscle biopsies were taken from five healthy men who had participated in a previous four-week HFrD study, during which insulin sensitivity (hyperinsulinaemic euglycaemic clamp), and intrahepatocellular lipids and IMCL were assessed before and after HFrD. The mRNA concentrations of 16 genes involved in lipid and carbohydrate metabolism were quantified before and after HFrD by real-time quantitative PCR. RESULTS: HFrD significantly (P

Published
2007

33. Activation of liver X receptors promotes lipid accumulation but does not alter insulin action in human skeletal muscle cells

Author

D. Pruneau, Etienne Lefai, Jennifer Rieusset, Martine Laville, Hubert Vidal, Emmanuel Disse, R. Rabasa-Lhoret, Julien Vouillarmet, Delphine Cozzone, Cyrille Debard, Nicolas Dif, and Nadège Ricard

Subjects
Adult, Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Receptors, Cytoplasmic and Nuclear, Type 2 diabetes, Biology, Fatty Acids, Nonesterified, Internal medicine, Internal Medicine, medicine, Humans, Insulin, Liver X receptor, Muscle, Skeletal, Pancreatic hormone, Liver X Receptors, Skeletal muscle, Promoter, Lipid metabolism, Middle Aged, medicine.disease, Orphan Nuclear Receptors, DNA-Binding Proteins, Endocrinology, medicine.anatomical_structure, Glucose, Lipogenesis, lipids (amino acids, peptides, and proteins), Female
Abstract

The aim of this study was to investigate the effects of liver X receptor (LXR) activation on lipid metabolism and insulin action in human skeletal muscle cells prepared from control subjects and from patients with type 2 diabetes.Cultured myotubes were obtained from muscle biopsies of 11 lean, healthy control subjects and ten patients with type 2 diabetes. The mRNA levels of LXR isoforms and lipogenic genes were estimated by RT-quantitative PCR, and the effects of LXR agonists on insulin action were evaluated by assays of protein kinase B serine 473 phosphorylation and glycogen synthesis.Both LXRalpha and LXRbeta were expressed in human skeletal muscle and adipose tissue and there was no difference in their mRNA abundance in tissues from patients with type 2 diabetes compared with control subjects. In cultured muscle cells, LXR activation by T0901317 strongly increased expression of the genes encoding lipogenic enzymes, including sterol regulatory element binding protein 1c, fatty acid synthase and stearoyl-CoA desaturase 1, and also promoted triglyceride accumulation in the presence of a high glucose concentration. Importantly, these effects on lipid metabolism did not affect protein kinase B activation by insulin. Furthermore, LXR agonists did not modify insulin action in muscle cells from patients with type 2 diabetes.These data suggest that LXR agonists may lead to increased utilisation of lipids and glucose in muscle cells without affecting the mechanism of action of insulin. However, the long-term consequences of triglyceride accumulation in muscle should be evaluated before the development of effective LXR-based therapeutic agents.

Published
2005

34. Changes in adiponectin receptor expression in muscle and adipose tissue of type 2 diabetic patients during rosiglitazone therapy

Author

Fredrik Karpe, Hubert Vidal, Sandy M. Humphreys, Yuji Matsuzawa, Tohru Funahashi, Garry D. Tan, Cyrille Debard, and Keith N. Frayn

Subjects
Adult, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Adipose tissue, Adipokine, Receptors, Cell Surface, White adipose tissue, Biology, Rosiglitazone, Insulin resistance, Double-Blind Method, Internal medicine, Internal Medicine, medicine, Humans, Hypoglycemic Agents, RNA, Messenger, Muscle, Skeletal, Aged, Adiponectin receptor 1, Cross-Over Studies, Adiponectin, Skeletal muscle, Middle Aged, medicine.disease, Lipid Metabolism, Lipids, Endocrinology, medicine.anatomical_structure, Adipose Tissue, Diabetes Mellitus, Type 2, Organ Specificity, Regional Blood Flow, Female, Thiazolidinediones, Receptors, Adiponectin, medicine.drug
Abstract

AIMS/HYPOTHESIS: Adiponectin is important in the regulation of insulin sensitivity in man. Its receptors, adipoR1 and R2, have recently been identified, but their expression in adipose tissue and their regulation in response to insulin sensitisation of diabetic patients have never been assessed. We therefore explored the regulation of adipoR1/R2 and adiponectin expression in adipose tissue and skeletal muscle, and of adiponectin plasma concentrations in response to insulin sensitisation by rosiglitazone. METHODS: Patients with type 2 diabetes were studied in a double-blind, placebo-controlled crossover study, using in vivo arteriovenous techniques of measuring adipose tissue and muscle blood flow, combined with measurement of adipose tissue and skeletal muscle gene expression. RESULTS: Rosiglitazone treatment increased adiponectin concentrations by 69%. Skeletal muscle adipoR1 expression was down-regulated from 109.0 (70.1-165.7) (median [interquartile range]) to 82.8 (63.6-89.3) relative units (p=0.04), but adipose tissue adipoR1 expression was up-regulated from 5.3 (4.4-9.4) to 11.2 (4.8-15.3) relative units (p=0.02) by rosiglitazone. In contrast to adipoR1 expression, adipoR2 expression was not altered by rosiglitazone in either of the tissues. The increase in adipose tissue adipoR1 expression with rosiglitazone was associated with increased postprandial triglyceride clearance (r=0.67, p=0.05), and increased fasting fatty acid output (r=0.78, p=0.01) measured in subcutaneous adipose tissue. CONCLUSIONS/INTERPRETATION: AdipoR1 expression is up-regulated in adipose tissue but down-regulated in skeletal muscle by rosiglitazone. These data suggest that adipoR1 plays a role in mediating the effects of adiponectin in specific tissues in relation to insulin sensitisation.

Published
2005

35. WY-14643 and 9-cis-retinoic acid induce IRS-2/PI 3-kinase signalling pathway and increase glucose transport in human skeletal muscle cells: differential effect in myotubes from healthy subjects and Type 2 diabetic patients

Author

Jennifer Rieusset, Cyrille Debard, V. Berbe, K. Bouzakri, Hubert Vidal, Martine Laville, Marina Roques, Service d'Hématologie Clinique (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), EUTHINE, Vanessa, and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Adult, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Glucose uptake, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Muscle Fibers, Skeletal, Retinoic acid, 030209 endocrinology & metabolism, Tretinoin, Retinoid X receptor, Biology, 03 medical and health sciences, chemistry.chemical_compound, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Insulin resistance, Reference Values, Internal medicine, Internal Medicine, medicine, Humans, Insulin, Muscle, Skeletal, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Myogenesis, Glucose transporter, Intracellular Signaling Peptides and Proteins, medicine.disease, Phosphoproteins, 3. Good health, [SDV] Life Sciences [q-bio], Endocrinology, Glucose, Pyrimidines, chemistry, Nuclear receptor, Diabetes Mellitus, Type 2, Insulin Receptor Substrate Proteins, Signal Transduction
Abstract

To determine the effects of peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor (RXR) agonists on insulin action, we investigated the effects of Wy-14643 and 9- cis-retinoic acid (9- cis-RA) on insulin signalling and glucose uptake in human myotubes.Primary cultures of differentiated human skeletal muscle cells, established from healthy subjects and Type 2 diabetic patients, were used to study the effects of Wy-14643 and 9- cis-RA on the expression and activity of proteins involved in the insulin signalling cascade. Glucose transport was assessed by measuring the rate of [(3)H]2-deoxyglucose uptake.Wy-14643 and 9- cis-RA increased IRS-2 and p85alpha phosphatidylinositol 3-kinase (PI 3-kinase) mRNA and protein expression in myotubes from non-diabetic and Type 2 diabetic subjects. This resulted in increased insulin stimulation of protein kinase B phosphorylation and increased glucose uptake in cells from control subjects. Myotubes from diabetic patients displayed marked alterations in the stimulation by insulin of the IRS-1/PI 3-kinase pathway. These alterations were associated with blunted stimulation of glucose transport. Treatment with Wy-14643 and 9- cis-RA did not restore these defects but increased the basal rate of glucose uptake.These results demonstrate that PPARalpha and RXR agonists can directly affect insulin signalling in human muscle cells. They also indicate that an increase in the IRS-2/PI 3-kinase pathway does not overcome the impaired stimulation of the IRS-1-dependent pathway and does not restore insulin-stimulated glucose uptake in myotubes from Type 2 diabetic patients.

Published
2004

36. Expression of key genes of fatty acid oxidation, including adiponectin receptors, in skeletal muscle of Type 2 diabetic patients

Author

Martine Laville, Yves Boirie, Cyrille Debard, V. Berbe, B. Morio-Liondore, Emmanuelle Loizon, C. Guillet, and Hubert Vidal

Subjects
Blood Glucose, Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Type 2 diabetes, Carbohydrate metabolism, Biology, Fatty Acids, Nonesterified, Models, Biological, Insulin resistance, Reference Values, Diabetes mellitus, Internal medicine, Internal Medicine, medicine, Humans, Muscle, Skeletal, Beta oxidation, Adiponectin, Fatty Acids, Acetyl-CoA carboxylase, Skeletal muscle, Middle Aged, medicine.disease, medicine.anatomical_structure, Endocrinology, Glucose, Diabetes Mellitus, Type 2, Female, Oxidation-Reduction
Abstract

Defective oxidation of long-chain fatty acids is a feature of insulin resistance and Type 2 diabetes. Our aim was to compare the expression levels of the genes encoding the major proteins and enzymes of this pathway in skeletal muscle of healthy subjects and Type 2 diabetic patients.The basal and insulin-regulated mRNA concentration of 16 genes was quantified using real-time PCR in skeletal muscle biopsies taken before and at the end of a 3-hour hyperinsulinaemic-euglycaemic clamp in healthy lean subjects and in insulin-resistant obese patients with manifest Type 2 diabetes.Acetyl CoA carboxylase-2 mRNA expression was increased 2.5-fold in the muscle of the diabetic patients. The expression of carnitine palmitoyl transferase-1, of the two adiponectin receptors and of genes involved in fatty acid transport and activation was not altered in diabetic patients. Hyperinsulinaemia for 3 hours increased the expression of several genes of fatty acid oxidation, including adiponectin receptor-1 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha. It also reduced pyruvate dehydrogenase 4 mRNA levels. The effects of insulin on gene expression were markedly altered in the muscle of Type 2 diabetic patients except for adiponectin receptor-1 and pyruvate dehydrogenase 4 mRNAs.The expression of adiponectin receptors was not altered in the muscle of Type 2 diabetic patients. The observed overexpression of acetyl CoA carboxylase-2 is consistent with the hypothesis that increased skeletal muscle malonyl CoA concentrations in Type 2 diabetes may contribute to the inhibition of long-chain fatty acid oxidation.

Published
2003

37. A 'futile cycle' induced by thiazolidinediones in human adipose tissue?

Author

Fredrik Karpe, Hubert Vidal, Sandy M. Humphreys, Cyrille Debard, Dominique Langin, Garry D. Tan, Claire Tiraby, and Keith N. Frayn

Subjects
medicine.medical_specialty, Insulin blood, business.industry, Futile cycle, Adipose tissue, General Medicine, medicine.disease, General Biochemistry, Genetics and Molecular Biology, Fatty acid-binding protein, law.invention, Clinical trial, Endocrinology, Randomized controlled trial, law, Internal medicine, Diabetes mellitus, medicine, business, Rosiglitazone, medicine.drug
Published
2003

39. P206 L’huile de palme, mais pas l’huile de colza ni l’huile de tournesol, prévient l’hyperperméabilité intestinale dans un modèle animal de syndrome de l’intestin irritable : mécanismes impliquant les cellules à mucus et la production de MUC2

Author

Pascale Plaisancié, Robert Ducroc, Cyrille Debard, B. Benoît, F. Kayal, M. Estienne, Emmanuelle Loizon, and Jérémie Bruno

Subjects
Nutrition and Dietetics, Endocrinology, Diabetes and Metabolism, Internal Medicine, Medicine (miscellaneous)
Published
2013
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40. The Eicosapentaenoic Acid Metabolite 15-Deoxy-δ12,14-Prostaglandin J3 Increases Adiponectin Secretion by Adipocytes Partly via a PPARγ-Dependent Mechanism

Author

Alain Géloën, Mairobys Socorro, Hubert Vidal, Michel Lagarde, Jennifer Lefils-Lacourtablaise, Michel Guichardant, Nathalie Bernoud-Hubac, Emmanuelle Loizon, Zury Domínguez, Cyrille Debard, and Patricia Daira

Subjects
Male, lcsh:Medicine, Adipose tissue, Peroxisome proliferator-activated receptor, Biochemistry, Mice, chemistry.chemical_compound, Molecular Cell Biology, Adipocytes, Macromolecular Structure Analysis, Signaling in Cellular Processes, Anilides, Adiponectin secretion, lcsh:Science, Epididymis, chemistry.chemical_classification, Multidisciplinary, Prostaglandin D2, Reverse Transcriptase Polymerase Chain Reaction, Fatty Acids, Lipids, Eicosapentaenoic acid, Adipose Tissue, Eicosapentaenoic Acid, Lipid Signaling, Medicine, lipids (amino acids, peptides, and proteins), Arachidonic acid, Adiponectin, Research Article, Signal Transduction, Polyunsaturated fatty acid, medicine.medical_specialty, Prostaglandin, Biology, Gas Chromatography-Mass Spectrometry, Lipid Mediators, 3T3-L1 Cells, Internal medicine, Lipid Structure, medicine, Animals, Nutrition, lcsh:R, Computational Biology, Lipid Metabolism, Dietary Fats, PPAR gamma, Metabolism, Endocrinology, chemistry, lcsh:Q
Abstract

The intake of ω-3 polyunsaturated fatty acids (PUFAs), which are abundant in marine fish meat and oil, has been shown to exert many beneficial effects. The mechanisms behind those effects are numerous, including interference with the arachidonic acid cascade that produces pro-inflammatory eicosanoids, formation of novel bioactive lipid mediators, and change in the pattern of secreted adipocytokines. In our study, we show that eicosapentaenoic acid (EPA) increases secreted adiponectin from 3T3-L1 adipocytes and in plasma of mice as early as 4 days after initiation of an EPA-rich diet. Using 3T3-L1 adipocytes, we report for the first time that 15-deoxy-δ(12,14)-PGJ3 (15d-PGJ3), a product of EPA, also increases the secretion of adiponectin. We demonstrate that the increased adiponectin secretion induced by 15d-PGJ3 is partially peroxisome proliferator-activated receptor-gamma (PPAR-γ)-mediated. Finally, we show that 3T3-L1 adipocytes can synthesize 15d-PGJ3 from EPA. 15d-PGJ3 was also detected in adipose tissue from EPA-fed mice. Thus, these studies provide a novel mechanism(s) for the therapeutic benefits of ω-3 polyunsaturated fatty acids dietary supplementation.

Published
2013
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