[Show abstract][Hide abstract] ABSTRACT: Nutrigenomics investigates relationships between nutrients and all genome-encoded molecular entities. This holistic approach requires systems biology to scrutinize the effects of diet on tissue biology. To decipher the adipose tissue (AT) response to diet induced weight changes we focused on key molecular (lipids and transcripts) AT species during a longitudinal dietary intervention. To obtain a systems model, a network approach was used to combine all sets of variables (bio-clinical, fatty acids and mRNA levels) and get an overview of their interactions. AT fatty acids and mRNA levels were quantified in 135 obese women at baseline, after an 8-week low calorie diet (LCD) and after 6 months of ad libitum weight maintenance diet (WMD). After LCD, individuals were stratified a posteriori according to weight change during WMD. A 3 steps approach was used to infer a global model involving the 3 sets of variables. It consisted in inferring intra-omic networks with sparse partial correlations and inter-omic networks with regularized canonical correlation analysis and finally combining the obtained omic-specific network in a single global model. The resulting networks were analyzed using node clustering, systematic important node extraction and cluster comparisons. Overall, AT showed both constant and phase-specific biological signatures in response to dietary intervention. AT from women regaining weight displayed growth factors, angiogenesis and proliferation signaling signatures, suggesting unfavorable tissue hyperplasia. By contrast, after LCD a strong positive relationship between AT myristoleic acid (a fatty acid with low AT level) content and de novo lipogenesis mRNAs was found. This relationship was also observed, after WMD, in the group of women that continued to lose weight. This original system biology approach provides novel insight in the AT response to weight control by highlighting the central role of myristoleic acid that may account for the beneficial effects of weight loss.
[Show abstract][Hide abstract] ABSTRACT: Brite adipocytes are inducible energy-dissipating cells expressing UCP1 which appear within white adipose tissue of healthy adult individuals. Recruitment of these cells represents a potential strategy to fight obesity and associated diseases. Using human Multipotent Adipose-Derived Stem cells, able to convert into brite adipocytes, we show that arachidonic acid strongly inhibits brite adipocyte formation via a cyclooxygenase pathway leading to secretion of PGE2 and PGF2α. Both prostaglandins induce an oscillatory Ca++ signaling coupled to ERK pathway and trigger a decrease in UCP1 expression and in oxygen consumption without altering mitochondriogenesis. In mice fed a standard diet supplemented with ω6 arachidonic acid, PGF2α and PGE2 amounts are increased in subcutaneous white adipose tissue and associated with a decrease in the recruitment of brite adipocytes. Our results suggest that dietary excess of ω6 polyunsaturated fatty acids present in Western diets, may also favor obesity by preventing the “browning” process to take place.
[Show abstract][Hide abstract] ABSTRACT: The breakdown of cellular fat stores fuels energy production and multiple anabolic processes. Albert et al. (2014) demonstrate that the lack of hormone-sensitive lipase, a member of the enzyme trio that catabolizes fat, has pronounced effects on lipid metabolism, glucose homeostasis, and cell signaling in humans.
[Show abstract][Hide abstract] ABSTRACT: Objectiveα-Lipoic acid (α-LA) is a natural occurring antioxidant with beneficial effects on obesity. The aim of this study was to investigate the putative effects of α-LA on triglyceride accumulation and lipogenesis in subcutaneous adipocytes from overweight/obese subjects and to determine the potential mechanisms involved.Design and Methods
Fully differentiated human subcutaneous adipocytes were treated with α-LA (100 and 250 µM) during 24 h for studying triglyceride content, de novo lipogenesis, and levels of key lipogenic enzymes. The involvement of AMP-activated protein kinase (AMPK) activation was also evaluated.Resultsα-LA down-regulated triglyceride content by inhibiting fatty acid esterification and de novo lipogenesis. These effects were mediated by reduction in fatty acid synthase (FAS), stearoyl-coenzyme A desaturase 1, and diacylglycerol O-acyltransferase 1 protein levels. Interestingly, α-LA increased AMPK and acetyl CoA carboxylase phosphorylation, while the presence of the AMPK inhibitor Compound C reversed the inhibition observed on FAS protein levels.Conclusionsα-LA down-regulates key lipogenic enzymes, inhibiting lipogenesis and reducing triglyceride accumulation through the activation of AMPK signaling pathway in human subcutaneous adipocytes from overweight/obese subjects.
[Show abstract][Hide abstract] ABSTRACT: j.celrep.2014.03.062 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). SUMMARY Adipose tissue fibrosis development blocks adipo-cyte hypertrophy and favors ectopic lipid accumula-tion. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in hu-mans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte meta-bolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a func-tional Toll-like receptor 4 on adipose tissue hemato-poietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, pro-motes adipose tissue fibrosis. Ex vivo, lipopolysac-charide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFb1. Together, these results indicate that obesity and en-dotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resis-tance, through immune cell Toll-like receptor 4. INTRODUCTION
[Show abstract][Hide abstract] ABSTRACT: Adipose tissue fibrosis development blocks adipocyte hypertrophy and favors ectopic lipid accumulation. Here, we show that adipose tissue fibrosis is associated with obesity and insulin resistance in humans and mice. Kinetic studies in C3H mice fed a high-fat diet show activation of macrophages and progression of fibrosis along with adipocyte metabolic dysfunction and death. Adipose tissue fibrosis is attenuated by macrophage depletion. Impairment of Toll-like receptor 4 signaling protects mice from obesity-induced fibrosis. The presence of a functional Toll-like receptor 4 on adipose tissue hematopoietic cells is necessary for the initiation of adipose tissue fibrosis. Continuous low-dose infusion of the Toll-like receptor 4 ligand, lipopolysaccharide, promotes adipose tissue fibrosis. Ex vivo, lipopolysaccharide-mediated induction of fibrosis is prevented by antibodies against the profibrotic factor TGFβ1. Together, these results indicate that obesity and endotoxemia favor the development of adipose tissue fibrosis, a condition associated with insulin resistance, through immune cell Toll-like receptor 4.
[Show abstract][Hide abstract] ABSTRACT: Triglycerides in adipose tissue are rapidly mobilized during times of energy needs via lipolysis, a catabolic process that plays important role in whole body triglyceride turnover. Lipolysis is regulated through cell surface receptors via neurotransmitters, hormones, and paracrine factors that activate various intracellular pathways. These pathways converge on the lipid droplet, the site of action of lipases and cofactors. Fat cell lipolysis is also involved in the pathogenesis of metabolic disorders, and recent human studies have underscored its role in disease states such as cancer cachexia and obesity-induced insulin resistance. We highlight here topics and findings with physiological and clinical relevance, namely lipid turnover in human fat cells and the role of lipolysis in cancer cachexia and obesity-induced insulin resistance.
Trends in Endocrinology and Metabolism 04/2014; · 8.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: To investigate if inulin-type fructan (ITF) prebiotics could counteract the thiazolidinedione (TZD, PPARγ activator) induced-fat mass gain, without affecting its beneficial effect on glucose homeostasis, in high-fat (HF) diet fed mice. Design and Methods: Male C57bl6/J mice were fed a HF diet alone or supplemented with ITF prebiotics (0.2g/day*mouse) or TZD (30mg pioglitazone/kg body weight*day) or both during 4 weeks. An insulin tolerance test was performed after 3 weeks of treatment. Results: As expected, pioglitazone improved glucose homeostasis and increased adiponectinaemia. Furthermore, it induced an over-expression of several PPARγ target genes in white adipose tissues. ITF prebiotics modulated the pioglitazone-induced PPARγ activation in a tissue-dependent manner. The co-treatment with ITF prebiotics and pioglitazone maintained the beneficial impact of TZD on glucose homeostasis and adiponectinaemia. Moreover, the combination of both treatments reduced fat mass accumulation, circulating lipids and hepatic triglyceride content, suggesting an overall improvement of metabolism. Finally, the co-treatment favored induction of white-to-brown fat conversion in subcutaneous adipose tissue (SAT), thereby leading to the development of brite adipocytes that could increase the oxidative capacity of the tissue. Conclusions: ITF prebiotics decrease adiposity and improve the metabolic response in HF fed mice treated with TZD.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Une association inverse entre le contenu en lipides intramyocellulaires et la sensibilité à l’insuline existe chez les sujets sédentaires. Cette relation disparait chez des individus entraînés en endurance et réfère au paradoxe des athlètes. Une dérégulation de l’expression des lipases musculaire pourrait contribuer à l’insulino-résistance. L’objectif de ce travail était d’étudier l’association entre contenu en lipides intramyocellulaires, expression des lipases, capacité oxydative et sensibilité à l’insuline chez des sédentaires, des athlètes et des obèses intolérants au glucose avant et après perte de poids.
Matériels et méthodes
Nous avons étudié des sujets de poids normal sédentaires et entraînés en endurance, ainsi que des obèses intolérants au glucose avant et après perte de poids induite par un régime hypocalorique. La sensibilité à l’insuline a été évaluée par clamp hyperinsulinémique-euglycémique, les triacylglycérols et diacylglycérols ont été mesurés par chromatographie gazeuse. L’expression des lipases a été étudiée par Western-blot et la capacité oxydative évaluée par mesure de l’activité citrate synthase.
Nos données montrent une forte association entre la sensibilité à l’insuline, la capacité oxydative et l’expression des lipases. Ces trois paramètres sont augmentés chez les athlètes et diminués chez les obèses comparés aux sédentaires. Nous observons une dissociation entre contenu en lipides intramyocellulaires toxiques et sensibilité à l’insuline avec une augmentation du contenu en diacylglycérols à la fois chez l’obèse et chez l’athlète. Nous observons également une diminution nette des triacylglycérols et diacylglycérols et de l’expression des lipases après perte de poids chez les obèses. Ces changements interviennent vis-à-vis d’une amélioration de la sensibilité à l’insuline et sans modification de la capacité oxydative musculaire.
Ces résultats suggèrent que les lipides intramyocellulaires totaux, l’expression des lipases et la capacité oxydative musculaire ne sont pas systématiquement associés, et ne constituent donc pas de bons marqueurs de la sensibilité à l’insuline.
[Show abstract][Hide abstract] ABSTRACT: Introduction
Les triglycérides intramusculaires constituent une source d’énergie importante pour le muscle squelettique notamment au cours d’un exercice physique. Des travaux récents suggèrent que l’ATGL (adipose triglyceride lipase) joue un rôle clé dans ce processus. Cependant, peu de données sont actuellement disponibles sur le contrôle de son activité. L’objectif de ce travail était d’étudier le rôle de la protéine G0/G1 Switch Gene 2 (G0S2), récemment décrite comme inhibitrice de l’ATGL dans le tissu adipeux, dans la régulation de la lipolyse et du métabolisme oxydatif musculaire.
Matériels et méthodes
L’expression de G0S2 a été diminuée, à l’aide de lentivirus contenant des shRNA, dans des cultures primaires de cellules musculaires squelettiques humaines (i.e. myotubes) issues de biopsies de rectus abdominis obtenues chez des volontaires sains. L’activité de l’ATGL, le contenu en triglycérides, la mobilisation et l’oxydation des acides gras, l’oxydation du glucose et la synthèse de glycogène ont été évalués à l’aide de substrats radiomarqués. Les approches métaboliques ont été complétées par des études d’immunofluorescence des mitochondries et d’expression de gènes clés par RT-qPCR.
Nos résultats montrent que G0S2 est exprimé dans les myotubes et qu’il inhibe l’activité de l’ATGL. Son invalidation induit une diminution du pool de triglycérides et une augmentation de la mobilisation et de l’oxydation des acides gras. L’oxydation du glucose et la synthèse de glycogène sont diminuées. L’augmentation du flux d’acides gras s’accompagne d’une hausse de la masse et du potentiel de membrane des mitochondries. Ces effets seraient potentiellement médiés par l’induction de gènes cibles du Peroxysome Proliferator Activated Receptor δ (PPARδ).
Ces résultats indiquent que G0S2 joue un rôle majeur dans la régulation de la lipolyse et du métabolisme oxydatif musculaire, en modulant le flux d’acides gras et l’expression de gènes cibles de PPARδ.
[Show abstract][Hide abstract] ABSTRACT: Context: Soluble CD163 was suggested as a biomarker of insulin sensitivity and CD163 mRNA expression representing macrophage content in adipose tissue (AT). Objective: The aim of this study was to investigate, in cross-sectional and prospective design, the relationship between sCD163 circulating levels and, CD163 mRNA expression in adipose tissue and insulin sensitivity assessed by euglycemic-hyperinsulinemic clamp. Design, Setting, Participants, and Interventions: Two cohorts of subjects were examined in the study. Cohort 1: forty-two women with wide range of BMI (17-48 kg/m(2)); Cohort 2: twenty-seven obese women, who followed a dietary intervention consisting of 1 month very low-calorie diet, and 5 months of weight-stabilization period. Main Outcome Measures: Serum levels of CD163 and mRNA expression of CD163 and CD68 in subcutaneous and visceral AT were determined, and insulin sensitivity (expressed as glucose disposal rate (GDR)) was measured in Cohort I. In Cohort 2, serum levels of CD163, mRNA expressions of CD163, CD68, and CD163-shedding factors (TACE and TIPM3) in subcutaneous AT were examined and GDR was measured before and during dietary intervention. Results: In Cohort 1, circulating sCD163 correlated with CD163 mRNA levels in both subcutaneous and visceral AT. sCD163 and CD163 mRNA expression in both fat depots correlated with GDR. In Cohort 2, the diet-induced changes of sCD163 levels did not correlate with those of CD163, CD 68, TACE and TIMP3 mRNA levels. Although the pattern of the diet-induced change of sCD163 paralleled that of GDR there was no correlation between the changes of these two variables. Conclusion: sCD163 correlates with CD163 mRNA expression in subcutaneous and visceral AT and with whole-body insulin sensitivity in steady state condition. These associations are not observed in respect to the diet-induced changes during weight-reducing hypocaloric diet.
The Journal of Clinical Endocrinology and Metabolism 01/2014; · 6.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Weight loss reduces risk factors associated with obesity. However, long-term metabolic improvement remains a challenge. We investigated quantitative gene expression of subcutaneous adipose tissue in obese individuals and its relationship with low calorie diet and long term weight maintenance induced changes in insulin resistance.
PLoS ONE 01/2014; 9(7):e98707. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the influence of substrate availability on fuel selection during exercise. Eight endurance-trained male cyclists performed 90-min exercise at 70 % of their maximal oxygen uptake in a cross-over design, either in rested condition (CON) or the day after 2-h exercise practised at 70 % of maximal oxygen uptake (EX). Subjects were given a sucrose load (0.75 g kg(-1) body weight) 45 min after the beginning of the 90-min exercise test. Lipolysis was measured in subcutaneous abdominal adipose tissue (SCAT) by microdialysis and substrate oxidation by indirect calorimetry. Lipid oxidation increased during exercise and tended to decrease during sucrose ingestion in both conditions. Lipid oxidation was higher during the whole experimental period in the EX group (p = 0.004). Interestingly, fuel selection, assessed by the change in respiratory exchange ratio (RER), was increased in the EX session (p = 0.002). This was paralleled by a higher rate of SCAT lipolysis reflected by dialysate glycerol, plasma glycerol, and fatty acids (FA) levels (p < 0.001). Of note, we observed a significant relationship between whole-body fat oxidation and dialysate glycerol in both sessions (r (2) = 0.33, p = 0.02). In conclusion, this study highlights the limiting role of lipolysis and plasma FA availability to whole-body fat oxidation during exercise in endurance-trained subjects. This study shows that adipose tissue lipolysis is a determinant of fuel selection during exercise in healthy subjects.
Journal of physiology and biochemistry 12/2013; · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: ß1-2-adrenergic receptors (AR) are key regulators of cardiac contractility and remodeling in response to catecholamines. ß3-AR expression is enhanced in diseased human myocardium, but its impact on remodeling is unknown.
Mice with cardiac myocyte-specific expression of human ß3-AR (ß3-TG) and wild-type (WT) littermates were used to compare myocardial remodeling in response to isoproterenol (Iso) or Angiotensin II (Ang II). ß3-TG and WT had similar morphometric and haemodynamic parameters at baseline. ß3-AR co-localized with caveolin-3, eNOS and nNOS in adult transgenic myocytes, which constitutively produced more cyclic GMP, detected with a new transgenic FRET sensor. Iso and Ang II produced hypertrophy and fibrosis in WT mice, but not in ß3-TG mice, which also had less re-expression of fetal genes and TGF-beta1. Protection from Iso-induced hypertrophy was reversed by non-specific nitric oxide synthase (NOS) inhibition at low dose Iso, and by preferential nNOS inhibition at high dose Iso. Adenoviral overexpression of ß3-AR in isolated cardiac myocytes also increased NO production and attenuated hypertrophy to Iso and phenylephrine (PE). Hypertrophy was restored upon NOS or Protein Kinase G inhibition. Mechanistically, ß3-AR overexpression inhibited PE-induced Nuclear Factor of Activated T-cells (NFAT) activation.
Cardiac-specific overexpression of ß3-AR does not affect cardiac morphology at baseline, but inhibits the hypertrophic response to neurohormonal stimulation in vivo and in vitro, through a NOS-mediated mechanism. Activation of the cardiac ß3-AR pathway may provide future therapeutic avenues for the modulation of hypertrophic remodeling.
[Show abstract][Hide abstract] ABSTRACT: The epidemic of obesity imposes unprecedented challenges on human adipose tissue (WAT) storage capacity that may benefit from adaptive mechanisms to maintain adipocyte functionality. Here, we demonstrate that changes in the regulatory feedback set point control of Insig1/SREBP1 represents an adaptive response that preserves WAT lipid homeostasis in obese and insulin resistant states.In our experiments we show that Insig1 mRNA expression decreases in WAT from mice with obesity-associated insulin resistance, from morbidly obese humans and in in vitro models of adipocyte insulin resistance. Insig1 down-regulation is part of an adaptive response that promotes the maintenance of SREBP1 maturation, facilitates lipogenesis and availability of appropriate levels of fatty acid unsaturation partially compensating the antilipogenic effect associated with insulin resistance. We describe for the first time the existence of this adaptive mechanism in WAT, which involves Insig1/SREBP1 and preserves the degree of lipid unsaturation under conditions of obesity-induced insulin resistance. These adaptive mechanisms contribute to maintain lipid desaturation through preferential SCD1 regulation and facilitate fat storage in WAT, despite on-going metabolic stress.
[Show abstract][Hide abstract] ABSTRACT: Accumulation of adipose tissue in lower body lowers risk of cardiovascular and metabolic disorders. The molecular basis of this protective effect of gluteofemoral depot is not clear. The aim of this study was to compare the profile of expression of inflammation-related genes in subcutaneous gluteal (sGAT) and abdominal (sAAT) adipose tissue at baseline and in response to multiphase weight-reducing dietary intervention (DI). 14 premenopausal healthy obese women underwent a 6 months´ DI consisting of 1 month very-low-calorie-diet (VLCD), subsequent 2 months' low-calorie-diet and 3 months' weight maintenance diet (WM). Paired samples of sGAT and sAAT were obtained before and at the end of VLCD and WM periods. mRNA expression of 17 genes (macrophage markers, cytokines) was measured using RT-qPCR on chip-platform. At baseline, there were no differences in gene expression of macrophage markers and cytokines between sGAT and sAAT. The dynamic changes induced by DI were similar in both depots for all genes except for three cytokines (IL6, IL10, CCL2) that differed in their response during weight maintenance phase. The results show that, in obese women, there are no major differences between sGAT and sAAT in expression of inflammation-related genes at baseline conditions and in response to the weight-reducing DI.
Physiological research / Academia Scientiarum Bohemoslovaca 11/2013; · 1.49 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context:Skeletal muscle lipase and intramyocellular triglyceride (IMTG) play a role in obesity-related metabolic disorders.Objectives:The aim of the present study was to investigate the impact of 8 weeks of endurance exercise training on IMTG content and lipolytic proteins in obese male subjects.Design and Volunteers:Ten obese subjects completed an 8-week supervised endurance exercise training intervention in which vastus lateralis muscle biopsy samples were collected before and after training.Main Outcome Measures:Clinical characteristics and ex vivo substrate oxidation rates were measured pre- and posttraining. Skeletal muscle lipid content and lipolytic protein expression were also investigated.Results:Our data show that exercise training reduced IMTG content by 42% (P < .01) and increased skeletal muscle oxidative capacity, whereas no change in total diacylglycerol content and glucose oxidation was found. Exercise training up-regulated adipose triglyceride lipase, perilipin (PLIN) 3 protein, and PLIN5 protein contents in skeletal muscle despite no change in mRNA levels. Training also increased hormone sensitive-lipase Ser660 phosphorylation. No significant changes in comparative gene identification 58, G0/G1 switch gene 2, and PLIN2 protein and mRNA levels were observed in response to training. Interestingly, we noted a strong relationship between skeletal muscle comparative gene identification 58 and mitochondrial respiratory chain complex I protein contents at baseline (r = 0.87, P < .0001).Conclusions:Endurance exercise training coordinately up-regulates fat oxidative capacity and lipolytic protein expression in skeletal muscle of obese subjects. This physiological adaptation probably favors fat oxidation and may alleviate the lipotoxic lipid pressure in skeletal muscle. Enhancement of IMTG turnover may be required for the beneficial metabolic effects of exercise in obesity.
The Journal of Clinical Endocrinology and Metabolism 10/2013; · 6.31 Impact Factor