Publications (18)105.52 Total impact
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Article: Visceral Fat Accumulation During Lipid Overfeeding Is Related to Subcutaneous Adipose Tissue Characteristics in Healthy Men.
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ABSTRACT: 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 overfeeding 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.The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor -
Article: n-3 PUFA added to high-fat diets affect differently adiposity and inflammation when carried by phospholipids or triacylglycerols in mice.
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ABSTRACT: 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. 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). 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. 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.Nutrition & Metabolism 01/2013; 10(1):23. · 2.88 Impact Factor -
Article: Dietary oxidized n-3 PUFA induce oxidative stress and inflammation: role of intestinal absorption of 4-HHE and reactivity in intestinal cells.
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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.The Journal of Lipid Research 08/2012; 53(10):2069-80. · 5.56 Impact Factor -
Article: Insulin-sensitizing effects on muscle and adipose tissue after dietary fiber intake in men and women with metabolic syndrome.
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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.The Journal of clinical endocrinology and metabolism 06/2012; 97(9):3326-32. · 6.50 Impact Factor -
Article: Gender differences in transcriptional signature of developing rat testes and ovaries following embryonic exposure to 2,3,7,8-TCDD.
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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.PLoS ONE 01/2012; 7(7):e40306. · 4.09 Impact Factor -
Article: Oil composition of high-fat diet affects metabolic inflammation differently in connection with endotoxin receptors in mice.
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ABSTRACT: Low-grade inflammation observed in obesity is a risk factor for cardiovascular disease. Recent studies revealed that this would be linked to gut-derived endotoxemia during fat digestion in high-fat diets, but nothing is known about the effect of lipid composition. The study was designed to test the impact of oil composition of high-fat diets on endotoxin metabolism and inflammation in mice. C57/Bl6 mice were fed for 8 wk with chow or isocaloric isolipidic diets enriched with oils differing in fatty acid composition: milk fat, palm oil, rapeseed oil, or sunflower oil. In vitro, adipocytes (3T3-L1) were stimulated or not with lipopolysaccharide (LPS; endotoxin) and incubated with different fatty acids. In mice, the palm group presented the highest level of IL-6 in plasma (P < 0.01) together with the highest expression in adipose tissue of IL-1β and of LPS-sensing TLR4 and CD14 (P < 0.05). The higher inflammation in the palm group was correlated with a greater ratio of LPS-binding protein (LBP)/sCD14 in plasma (P < 0.05). The rapeseed group resulted in higher sCD14 than the palm group, which was associated with lower inflammation in both plasma and adipose tissue despite higher plasma endotoxemia. Taken together, our results reveal that the palm oil-based diet resulted in the most active transport of LPS toward tissues via high LBP and low sCD14 and the greatest inflammatory outcomes. In contrast, a rapeseed oil-based diet seemed to result in an endotoxin metabolism driven toward less inflammatory pathways. This shows that dietary fat composition can contribute to modulate the onset of low-grade inflammation through the quality of endotoxin receptors.AJP Endocrinology and Metabolism 11/2011; 302(3):E374-86. · 4.75 Impact Factor -
Article: GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia.
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ABSTRACT: 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. Phenotypic expression and functional consequences of these two mutations were studied. We performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells. 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. 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.The Journal of clinical endocrinology and metabolism 08/2011; 96(10):E1675-9. · 6.50 Impact Factor -
Article: Genetic association and gene expression analysis identify FGFR1 as a new susceptibility gene for human obesity.
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ABSTRACT: Previous studies suggest a role for fibroblast growth factor receptor 1 (FGFR1) in the regulation of energy balance. Our objective was to investigate whether FGFR1 is an obesity gene by genetic association and functional studies. 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. General community and referral centers for specialized care was the setting for the study. 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. 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. 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). FGFR1 is a novel obesity gene that may promote obesity by influencing adipose tissue and the hypothalamic control of appetite.The Journal of clinical endocrinology and metabolism 03/2011; 96(6):E962-6. · 6.50 Impact Factor -
Article: Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent of energy intake.
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ABSTRACT: The mechanisms underlying body weight evolution after diet-induced weight loss are poorly understood. 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. 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. 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. 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.American Journal of Clinical Nutrition 10/2010; 92(4):975-84. · 6.67 Impact Factor -
Article: Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans.
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ABSTRACT: 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.AJP Endocrinology and Metabolism 03/2010; 298(6):E1161-9. · 4.75 Impact Factor -
Article: Tpl2 kinase is upregulated in adipose tissue in obesity and may mediate interleukin-1beta and tumor necrosis factor-{alpha} effects on extracellular signal-regulated kinase activation and lipolysis.
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ABSTRACT: 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. 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. IkappaB kinase-(IKK)-beta inhibition prevented mitogen-activated protein (MAP) kinase kinase (MEK)/ERK1/2 activation in response to interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha but not insulin in 3T3-L1 and human adipocytes, suggesting that IKKbeta 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-1beta and TNF-alpha activated Tpl2 and regulated its expression through an IKKbeta 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-alpha expression. 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.Diabetes 10/2009; 59(1):61-70. · 8.29 Impact Factor -
Article: High protein intake reduces intrahepatocellular lipid deposition in humans.
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ABSTRACT: 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. 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. 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. 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). 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.American Journal of Clinical Nutrition 09/2009; 90(4):1002-10. · 6.67 Impact Factor -
Article: Rapid down-regulation of mitochondrial fat metabolism in human muscle after training cessation is dissociated from changes in insulin sensitivity.
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ABSTRACT: The association between impairment in mitochondrial muscle fat oxidative capacity (OX(FA)) and occurrence of insulin resistance was examined in 14 healthy trained men (age, 24+/-4 yr) submitted to 4 weeks of training cessation. Training stop induced a significant decrease in mRNA levels of proteins involved in muscle fat metabolism, particularly PPARalpha (-58%, P<0.01) and PGC-1alpha (-30%, P<0.05), a 21% reduction in OX(FA) (P<0.01), and reduced fat oxidation during moderately intense exercise (P<0.05). In contrast, there was no significant alteration in insulin sensitivity. In conclusion, decline in OX(FA) is a rapid metabolic event following training cessation. It is involved in the regulation of whole body fat balance but not in the deterioration of insulin sensitivity.FEBS letters 09/2009; 583(17):2927-33. · 3.54 Impact Factor -
Article: Effects of docosahexaenoic acid on some megakaryocytic cell gene expression of some enzymes controlling prostanoid synthesis.
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ABSTRACT: 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.Biochemical and Biophysical Research Communications 09/2008; 372(4):924-8. · 2.48 Impact Factor -
Article: Microarray analyses of SREBP-1a and SREBP-1c target genes identify new regulatory pathways in muscle.
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ABSTRACT: 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.Physiological Genomics 07/2008; 34(3):327-37. · 2.73 Impact Factor -
Article: Short-term activation of peroxysome proliferator-activated receptor beta/delta increases fatty acid oxidation but does not restore insulin action in muscle cells from type 2 diabetic patients.
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ABSTRACT: Defective fatty acid oxidation in skeletal muscle is one of the possible causes of insulin resistance. Peroxisome proliferator-activated receptor beta activators are strong inducers of fatty acid oxidation. The aim of this study was to verify whether activation of fatty acid oxidation by PPARbeta agonists in human skeletal muscle cells prepared from type 2 diabetic patients could improve the reduced responses to insulin that characterized this cell model. GW0742 (10 nM) significantly increased fatty acid oxidation and oxidative gene expression in myotubes prepared from both healthy subjects and type 2 diabetic patients. In cells from control subjects, incubation with the agonist for 48 h affected neither insulin-induced rate of glycogen synthesis nor the phosphorylation state of protein kinase B (PKB serine 473). Myotubes from type 2 diabetic patients displayed marked reduction in the effects of insulin on glycogen synthesis and on PKB phosphorylation. However, treatment with PPARbeta agonists did not restore these defects. Therefore, these results indicate that induction of fatty acid oxidation with PPARbeta activators during short-term exposition is not sufficient to correct for insulin resistance in muscle cells from type 2 diabetic patients. This suggests that additional studies are needed to better characterize the link between fatty acid oxidation and insulin sensitivity in humans.Journal of Molecular Medicine 10/2006; 84(9):747-52. · 4.67 Impact Factor -
Article: A "futile cycle" induced by thiazolidinediones in human adipose tissue?
Nature Medicine 08/2003; 9(7):811-2; author reply 812. · 22.46 Impact Factor -
Article: Adipose tissue transcriptome reflects variations between subjects with continued weight loss and subjects regaining weight 6 mo after caloric restriction independent …
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ABSTRACT: on behalf of the DiOGenes Project 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 con-tent. In addition to anthropometric and plasma markers, SAT bi-opsies were taken at the beginning [clinical investigation day (CID) 2] and end (CID3) of the weight follow-up period. Microarray anal-ysis 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 suc-cessful and unsuccessful groups were mainly due to weight varia-tions rather than to differences in dietary macronutrient content. An analysis of covariance with total energy intake as a covariate iden-tified 1338 differentially expressed genes. Cellular growth and pro-liferation, 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 transcrip-tome. Although cell proliferation may be detrimental, a greater mi-tochondrial energy gene expression is suggested as being beneficial for weight control. This trial was registered at clinicaltrials.gov as NCT00390637. Am J Clin Nutr 2010;92:975–84.
Top co-authors
Top Journals
Institutions
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2013
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Institut National des Sciences Appliquées de Lyon
Lyon, Rhone-Alpes, France
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2012
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Université de Lyon
Lyon, Rhone-Alpes, France
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2011
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French National Institute for Agricultural Research
Paris, Ile-de-France, France
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2006
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Université Claude Bernard Lyon 1
Villeurbanne, Rhone-Alpes, France
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