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International audience; Diet-induced obesity (DIO) reduces the orosensory perception of lipids in rodents and in some humans. Although bariatric surgery partially corrects this alteration, underlying mechanisms remain poorly understood. To explore whether metabolic changes might explain this fat taste disturbance, plasma metabolome analyses, two-bottle choice tests and fungiform papillae (Fun) counting were performed in vertical sleeve gastrectomized (VSG) mice and sham-operated controls. An exploratory clinic study was also carried out in adult patients undergone a VSG. In mice, we found that (i) the VSG reduces both the plasma neurotoxic signature due to the tryptophan/kynurenine (Trp/Kyn) pathway overactivation and the failure of fat preference found in sham-operated DIO mice, (ii) the activity of Trp/Kyn pathway is negatively correlated to the density of Fun, and (iii) the pharmacological inhibition of the Kyn synthesis mimics in non-operated DIO mice the positive effects of VSG (i.e., decrease of Kyn synthesis, increase of Fun number, improvement of the fat taste perception). In humans, a reduction of the plasma Kyn level is only found in patients displaying a post-surgery improvement of their fat taste sensitivity. Altogether these data provide a plausible metabolic explanation to the degradation of the orosensory lipid perception observed in obesity.

International audience; Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes lysosomal degradation of the LDL receptor and is a key regulator of cholesterol metabolism. After the liver, the small intestine is the second organ that highly expresses PCSK9. However, the small intestine's ability to secrete PCSK9 remains a matter of debate. While liver-specific PCSK9-deficient mice present no PCSK9 in systemic blood, human intestinal Caco-2 cells can actively secrete PCSK9. This raises the possibility for active intestinal secretion via the portal blood. Here, we aimed to determine whether enterocytes can secrete PCSK9 using in vitro, ex vivo, and in vivo approaches. We first observed that PCSK9 secretion from Caco-2 cells was biphasic and dependent on Caco-2 maturation status. Transcriptional analysis suggested that this transient reduction in PCSK9 secretion might be due to loss of SREBP2-mediated transcription of PCSK9. Consistently, PCSK9 secretion was not detected ex vivo in human or mouse intestinal biopsies mounted in Ussing chambers. Finally, direct comparison of systemic versus portal blood PCSK9 concentrations in WT or liver-specific PCSK9-deficient mice confirmed the inability of the small intestine to secrete PCSK9 into the portal compartment. Altogether, our data demonstrate that mature enterocytes do not secrete PCSK9 and reinforce the central role of the liver in the regulation of the concentration of circulating PCSK9 and consequently of cellular LDL receptors.

Objective: Increased postprandial lipemia (PPL) is an independent risk factor for atherosclerotic cardiovascular diseases. PCSK9 (Proprotein convertase subtilisin kexin type 9) is an endogenous inhibitor of the LDLR (low-density lipoprotein receptor) pathway. We previously showed that PCSK9 inhibition in mice reduces PPL. However, the relative contribution of intracellular intestinal PCSK9 or liver-derived circulating PCSK9 to this effect is still unclear. Approach and Results: To address this issue, we generated the first intestine-specific Pcsk9 -deficient (i- Pcsk9 −/− ) mouse model. PPL was measured in i- Pcsk9 −/− as well as in wild-type and streptozotocin-induced diabetic mice following treatment with a PCSK9 monoclonal antibody (alirocumab). Blocking the circulating form of PCSK9 with alirocumab significantly reduced PPL, while overexpressing human PCSK9 in the liver of full Pcsk9 −/− mice had the opposite effect. Alirocumab regulated PPL in a LDLR-dependent manner as this effect was abolished in Ldlr −/− mice. In contrast, i- Pcsk9 −/− mice did not exhibit alterations in plasma lipid parameters nor in PPL. Finally, PPL was highly exacerbated by streptozotocin-induced diabetes mellitus in Pcsk9 +/+ but not in Pcsk9 −/− mice, an effect that was mimicked by the use of alirocumab in streptozotocin-treated Pcsk9 +/+ mice. Conclusions: Taken together, our data demonstrate that PPL is significantly altered by full but not intestinal PCSK9 deficiency. Treatment with a PCSK9 monoclonal antibody mimics the effect of PCSK9 deficiency on PPL suggesting that circulating PCSK9 rather than intestinal PCSK9 is a critical regulator of PPL. These data validate the clinical relevance of PCSK9 inhibitors to reduce PPL, especially in patients with type 2 diabetes mellitus.

International audience; OBJECTIVE: Bariatric surgery appears as the most efficient therapeutic alternative in morbidly obese patients. In addition to its efficiency to decrease body weight, it also improves metabolic complications associated to morbid obesity, including dyslipidemia. Although the cholesterol-lowering effect varies with the bariatric procedures, the underlying molecular mechanisms remain poorly defined. This study aims to assess the consequence of both restrictive (sleeve gastrectomy; SG) and malabsorptive (Roux-en-Y gastric bypass; RYGB) procedures on cholesterol metabolism in mice. SUBJECTS: Ten-week-old C57BL6/J males were fed with a high-fat diet for 8-14 weeks before sleeve or RYGB surgery. RESULTS: SG has a modest and transient effect on plasma cholesterol levels, linked to a reduction in food intake. In contrast, modified RYGB led to a sustained ≈35% reduction in plasma cholesterol concentrations with a drastic increase in fecal cholesterol output. Mechanistically, RYGB exerts a synergystic effect on cholesterol metabolism by inducing the trans-intestinal cholesterol efflux and reducing the intestinal cholesterol absorption. CONCLUSIONS: In mice, RYGB, but not sleeve, strongly favors plasma cholesterol elimination by concomitantly increasing trans-intestinal cholesterol excretion and by decreasing intestinal cholesterol absorption. Our models open new perspective for deciphering the hypocholesterolemic effects of bariatric procedures.

Resume Discipline Experimental/mecanismes cellulaires et moleculaires. Introduction et but de l’etude La surconsommation d’aliments riches en sucres et en graisses est un des facteurs de risque d’obesite. Ces aliments s’averent fortement attractifs probablement en raison de la satisfaction hedonique qu’ils procurent. Ce constat suppose l’existence d’une detection precoce et selective de ces nutriments des la mise en bouche des aliments orientant les choix alimentaires. Chez le rat, le fait que des animaux rendus obeses par regime surconsomment les aliments denses en energie suggere que leur detection oro-sensorielle des sucres et lipides pourrait etre perturbee. Ce phenomene est reversible puisque des rats initialement obeses ayant subi un by-pass gastrique Roux en Y delaissent les aliments riches en sucres et graisses au profit d’un regime pauvre en energie. Les mecanismes a l’origine de ces modifications comportementales sont actuellement mal connus. Pour tenter de les elucider, nous avons transpose chez la souris deux chirurgies bariatriques largement pratiquees chez l’Homme : la sleeve gastrectomie (SG, chirurgie restrictive) et le by-pass gastrique Roux en Y (RYGBm) connues pour impacter les choix alimentaires. Utilisant ces modeles, nous avons tente de repondre a la question suivante : Quelle est l’evolution de la detection oro-sensorielle d’un sucre (le saccharose) chez des souris obeses ayant subies une SG ou un RYGBm ? Materiel et methodes Cette etude a ete validee par les comites ethiques ad hoc. Pour chaque modele de chirurgie, 3 groupes de souris ont ete constitues : des temoins operes a blanc en regime standard (T-Std) ou rendus obeses par regime gras (T-HFD) et des souris obeses operees (SG ou RYGBm) maintenues en regime HFD apres operation pour cibler uniquement l’impact de la chirurgie. La composition corporelle (RMN quantitative) et l’intolerance au glucose (OGTT) ont ete evaluees avant et apres chirurgie. La sensibilite orosensorielle du sucre a ete analysee au moyen d’un gustometre permettant l’analyse de la reponse (lapees) des animaux a differentes concentrations de saccharose. Resultats et analyse statistique La SG et le RYGBm induisent une diminution significative de la masse grasse et ameliorent la sensibilite au glucose des souris initialement obeses en depit du fait qu’elles soient maintenues en regime HFD. Globalement, la chute du nombre total de lapees par session de 30 min, du nombre de lapees/10 sec en fonction de la concentration de saccharose et du seuil de detection oro-sensoriel du saccharose observe chez les T-HFD vs T-Std est partiellement corrigee par les 2 chirurgies, le RYGBm s’averant plus efficace que la SG. Conclusion Ces donnees montrent que la chirurgie bariatrique ameliore significativement la perception oro-sensorielle du sucre chez la souris initialement obese en depit de son maintien sur un regime obesogene. Cette observation, inedite pour cette espece, ouvre de nouvelles perspectives d’etude du changement du comportement alimentaire au cours de l’obesite.

International audience; High-protein-low-carbohydrate (HP-LC) diets have become widespread. Yet their deleterious consequences, especially on glucose metabolism and arteries, have already been underlined. Our previous study (2) has already shown glucose intolerance with major arterial dysfunction in very old mice subjected to an HP-LC diet. The hypothesis of this work was that this diet had an age-dependent deleterious metabolic and cardiovascular outcome. Two groups of mice, young and adult (3 and 6 mo old), were subjected for 12 wk to a standard or to an HP-LC diet. Glucose and lipid metabolism was studied. The cardiovascular system was explored from the functional stage with Doppler-echography to the molecular stage (arterial reactivity, mRNA, immunohistochemistry). Young mice did not exhibit any significant metabolic modification, whereas adult mice presented marked glucose intolerance associated with an increase in resistin and triglyceride levels. These metabolic disturbances were responsible for cardiovascular damages only in adult mice, with decreased aortic distensibility and left ventricle dysfunction. These seemed to be the consequence of arterial dysfunctions. Mesenteric arteries were the worst affected with a major oxidative stress, whereas aorta function seemed to be maintained with an appreciable role of cyclooxygenase-2 to preserve endothelial function. This study highlights for the first time the age-dependent deleterious effects of an HP-LC diet on metabolism, with glucose intolerance and lipid disorders and vascular (especially microvessels) and cardiac functions. This work shows that HP-LC lead to equivalent cardiovascular alterations, as observed in very old age, and underlines the danger of such diet.

International audience; Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for heart failure. T2DM is associated with altered cardiac energy metabolism, leading to ectopic lipid accumulation and glucose overload, the exact contribution of these two parameters remaining unclear. To provide new insight into the mechanism driving the development of diabetic cardiomyopathy, we studied a unique model of T2DM: lipodystrophic Bscl2(-/-) (seipin knockout [SKO]) mice. Echocardiography and cardiac magnetic resonance imaging revealed hypertrophic cardiomyopathy with left ventricular dysfunction in SKO mice, and these two abnormalities were strongly correlated with hyperglycemia. Surprisingly, neither intramyocardial lipid accumulation nor lipotoxic hallmarks were detected in SKO mice. [(18)F]Fludeoxyglucose positron emission tomography showed increased myocardial glucose uptake. Consistently, the O-GlcNAcylated protein levels were markedly increased in an SKO heart, suggesting a glucose overload. To test this hypothesis, we treated SKO mice with the hypoglycemic sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin and the insulin sensitizer pioglitazone. Both treatments reduced the O-GlcNAcylated protein levels in SKO mice, and dapagliflozin successfully prevented the development of hypertrophic cardiomyopathy. Our data demonstrate that glucotoxicity by itself can trigger cardiac dysfunction and that a glucose-lowering agent can correct it. This result will contribute to better understanding of the potential cardiovascular benefits of SGLT2 inhibitors.

International audience; Obesity is a major public health issue, with a prevalence of 4 to 28% for men and 6.2 to 36.5% for women in Europe (from 2003 to 2008). Morbid obesity is frequently associated with metabolic complications, such as type 2 diabetes, hypertension, and dyslipidemia, reducing life expectancy and quality. In the absence of any effective noninvasive treatments, bariatric surgery is a valuable therapeutic option for patients with morbid obesity (body mass index (BMI) \textgreater40 kg/m(2)), leading to long-term, sustained weight loss and improvements in metabolic complications. However, the underlying cellular and molecular mechanisms sustaining the beneficial effects of bariatric surgery are not yet fully understood. Due to the numerous genetically-modified strains available, the mouse model is the most convenient animal model to explore the molecular mechanisms behind the pleiotropic beneficial effects of bariatric surgeries. Here, we detailed the optimized healthcare methods and surgical protocols in mice for the two most widely-used bariatric surgeries: the sleeve gastrectomy and the modified Roux-en-Y gastric bypass. Deciphering the molecular mechanisms underlying the therapeutic effects of bariatric surgeries offers the promise of identifying new therapeutics targets.

IF 3.947; International audience; BACKGROUND: Increased lipopolysaccharide (LPS) translocation due to altered intestinal permeability has been suggested as a mechanism for obesity-associated insulin resistance. The goal of this study was to assess the effect of sleeve gastrectomy (SG) on intestinal barrier permeability in diet-induced obese mice.MATERIALS AND METHODS: Four weeks after surgery, the effects of SG on intestinal permeabilities were assessed ex vivo and in vivo in male C57Bl/6J mice fed a high-fat diet. Gene expression of tight junction proteins and inflammatory cytokines was measured in jejunum, colon, liver, and inguinal adipose tissue. Plasma LPS was quantified by HPLCMS/MS spectrometry.RESULTS: SG significantly reduced body weight and improved glucose homeostasis, as expected. SG decreased paracellular (p = 0.01) and transcellular permeability (p = 0.03) in the jejunum; and increased mRNA levels of the tight junction proteins Jam A (p = 0.02) and occludin (p = 0.01). In contrast in the distal colon, paracellular permeability tended to be increased (p = 0.07) while transcellular permeability was significantly induced (p = 0.03) after SG. In vivo, the paracellular permeability was significantly increased 3 weeks after SG (p = 0.02). Plasma LPS level were increased after SG (p = 0.03), as well as mRNA levels of adipose and hepatic inflammatory markers (p = 0.02).CONCLUSIONS: SG significantly modifies intestinal permeability in a differential manner between the proximal and distal intestine. These changes promote LPS translocation in plasma, induce a low-grade pro-inflammatory state in adipose tissue and liver, but do not impair the SG-induced glucose homeostasis improvement.

International audience; Fibroblast growth factor 21 (FGF21) was shown to improve metabolic homeostasis, at least partly by controlling white adipocyte profile and adiponectin secretion. Here, we studied its effect on adipocyte dysfunction in the context of Berardinelli-Seip congenital lipodystrophy (BSCL) linked to seipin deficiency. Bscl2(-/-) mice displayed a progressive adipose tissue loss with aging as evidenced by the altered profile of residual fat pads and the decrease in adiponectin plasma levels in 12- vs. 4-week-old animals. Aiming to prevent this impairment, we treated 6-week-old Bscl2(-/-) mice with an FGF21 analog (LY2405319) for a period of 28 days. FGF21 treatment increased adiponectin plasma levels and normalized insulin sensitivity in Bscl2(-/-) mice by improving the white adipose tissue gene expression pattern. To further decipher the molecular pathways altered by seipin deficiency in mature adipocytes, we developed a unique inducible seipin knockdown cell line (SKD). SKD showed chronic activation of the p38 MAPK pathway associated with apoptotic cell death. Interestingly, FGF21 treatment exerted an antistress effect on SKD cells, reducing p38 MAPK phosphorylation and limiting mature adipocyte loss. Our data demonstrate that FGF21 treatment improves the metabolic profile of Bscl2(-/-) lipodystrophic mice, partly by improving mature adipocyte maintenance through suppression of cellular stress via inhibition of p38 MAPK activity.

International audience; Loss-of-function mutations in BSCL2 are responsible for Berardinelli-Seip congenital lipodystrophy, a rare disorder characterized by near absence of adipose tissue associated with insulin resistance. Seipin-deficient (Bscl2 −/−) mice display an almost total loss of white adipose tissue (WAT) with residual brown adipose tissue (BAT). Previous cellular studies have shown that seipin deficiency alters white adipocyte differentiation. In this study, we aimed to decipher the consequences of seipin deficiency in BAT. Using a brown adipocyte cell-line, we show that seipin knockdown had very little effect on adipocyte differentiation without affecting insulin sensitivity and oxygen consumption. However, when submitted to cold acclimation or chronic β3 agonist treatment, Bscl2 −/− mice displayed altered thermogenic capacity, despite several signs of BAT remodeling. Under cold activation, Bscl2 −/− mice were able to maintain their body temperature when fed ad libitum, but not under short fasting. At control temperature (i.e. 21 °C), fasting worsened Bscl2 −/− BAT properties. Finally, Bscl2 −/− BAT displayed obvious signs of insulin resistance. Our results in these lipodystrophic mice strongly suggest that BAT activity relies on WAT as an energetic substrate provider and adipokine-producing organ. Therefore, the WAT/BAT dialogue is a key component of BAT integrity in guaranteeing its response to insulin and cold-activated adrenergic signals. Berardinelli and Seip congenital lipodystrophy (BSCL) is a rare autosomal genetic disease characterized by an almost complete lack of white adipose tissue (WAT) 1,2. BSCL is associated with metabolic disturbances, including insulin resistance, hypertriglyceridaemia, and liver steatosis. The most severe form of BSCL is caused by bi-allelic mutations in BSCL2, which encodes seipin, an endoplasmic reticulum (ER) protein of unknown function 3. Seipin deficiency strongly impairs adipocyte differentiation in vitro 4,5. In yeast and in cultured human cells, seipin deficiency alters lipid droplet (LD) morphology, with either a few giant or multiple small LDs 6–9. Recently, seipin was reported to be essential for the initiation of LD formation in yeast 10. In accordance with a potential role in triglyc-eride (TG) synthesis pathway, seipin was shown to interact with 1-acylglycerol-3-phosphate O-acyltransferase 2 (AGPAT2) and lipin 1 11,12. Finally, seipin has been shown to promote TG storage through an interaction with the calcium pump SERCA2 in drosophila 13. Nevertheless, the precise biological role of seipin and the exact pathways in which it is implicated remain unclear. A major breakthrough in the understanding of the pathophysiology of BSCL2 came with the generation of global knockout (KO) mice for Bscl2. Bscl2 −/− mice display severe lipodystrophy, with at least a 90% decrease in WAT mass and the development of insulin resistance and hepatic steatosis, thus recapitulating the main features of the human BSCL phenotype 14–16. Adipose-specific Bscl2 −/− mice exhibit progressive lipodystrophy associated with similar metabolic complications 17 , whereas the transgenic overexpression of Bscl2 in WAT from Bscl2 −/− mice is sufficient to rescue the phenotype 18. Finally, thiazolidinedione (TZD) treatment in global or adipose-specific Bscl2 KO mice promotes an increase in WAT mass, leading to an improvement of the metabolic 1

Objective— Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT. Approach and Results— We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X 1 and P2Y 6 was dominant. P2Y 6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6 −/− arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y 6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6 −/− mice were protected against MT elevation in myocardial infarction–induced heart failure. Although both P2Y 6 and P2Y 2 receptors contributed to calcium mobilization, P2Y 6 activation was mandatory for RhoA–GTP binding, myosin light chain, P42–P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43 +/− and P2rx7 −/− mesenteric resistance arteries. Conclusions— Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y 6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.

IF 4.942 (2013); International audience

International audience; Aging leads to a high prevalence of glucose intolerance and cardiovascular diseases, with oxidative stress playing a potential role. Resveratrol has shown promising effects on glucose tolerance and tends to improve endothelial function in elderly patients. Thioredoxin-interacting protein (TXNIP) was recently proposed as a potential link connecting glucose metabolism to oxidative stress. Here, we investigated the resveratrol-induced improvement of arterial aging phenotype in old mice and the expression of aortic TXNIP. Using an in vivo model of old mice with or without 3-month resveratrol treatment, we investigated the effects of resveratrol on age-related impairments from a cardiovascular Doppler analysis, to a molecular level, by studying inflammation and oxidative stress factors. We found a dual effect of resveratrol, with a decrease of age-related glucose intolerance and oxidative stress imbalance leading to reduced matrix remodeling that forestalls arterial aging phenotype in terms of intima-media thickness and arterial distensibility. These results provide the first evidence that aortic TXNIP mRNA and protein nuclear expressions are increased in the arterial aging and decreased by resveratrol treatment. In conclusion, we demonstrated that resveratrol helped to restore several aging impaired processes in old mice, with a decrease of aortic TXNIP mRNA and protein nuclear expressions

Introduction et but de l’etude Les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses morbides. Outre la perte de poids, ces chirurgies induisent une reduction significative des complications metaboliques associees, notamment les dyslipidemies. Cette etude vise a determiner chez la souris les consequences de 2 methodes de chirurgies bariatriques, i.e. la gastrectomie de type sleeve (sleeve) et de type bypass roux en Y (RYGB), sur les voies regulant le metabolisme du cholesterol. Materiel et methodes Des souris mâles C57BL6/J âgees de 10 semaines ont recu un regime hyperlipidique pendant 8 (sleeve) a 12 semaines (RYGB) avant les chirurgies. Les souris ont ete randomisees sur le poids et la cholesterolemie puis ont beneficie d’une chirurgie de type sham (laparotomie), sleeve ou d’un RYGB. Nous avons mesure les consequences des chirurgies sur le poids et le metabolisme glucidique et lipidique. L’analyse de l’excretion biliaire, transintestinale et fecale de cholesterol a ete determinee in vivo par spectrometrie de masse (GC-MS). Resultats et analyse statistique La duree operatoire moyenne mesuree a ete de 49,33 ± 5,1 minutes pour le groupe sleeve et de 93,63 ± 1,7 minutes pour le groupe RYGB. Quatorze jours apres chirurgie (j+14), la chirurgie de type sleeve et RYGB ont induit une reduction significative du poids corporel (respectivement −15,63 % et −25 % par rapport a la valeur mesuree avant la chirurgie [p Conclusion En conclusion, nous avons mis en place, avec succes, deux modeles de chirurgie bariatrique chez la souris. L’effet hypocholesterolemiant observe apres chirurgie de type sleeve est modeste et semble etre principalement lie a des modifications de la prise alimentaire. En revanche, la chirurgie de type RYGB induit une hypocholesterolemie marquee et une forte induction de l’excretion fecale de cholesterol.

International audience; Resveratrol is often described as a promising therapeutic molecule for numerous diseases, especially in metabolic and neurodegenerative disorders. While the mechanism of action is still debated, an increasing literature reports that resveratrol regulates the mitochondrial respiratory chain function. In a recent study we have identified mitochondrial complex I as a direct target of this molecule. Nevertheless, the mechanisms and consequences of such an interaction still require further investigation. In this study, we identified in silico by docking study a binding site for resveratrol at the nucleotide pocket of complex I. In vitro, using solubilized complex I, we demonstrated a competition between NAD+ and resveratrol. At low doses (

International audience; Aging leads to increased insulin resistance and arterial dysfunction, with oxidative stress playing an important role. This study explored the metabolic and arterial effects of a chronic treatment with resveratrol, an antioxidant polyphenol compound that has been shown to restore insulin sensitivity and decrease oxidative stress, in old mice with or without a high-protein diet renutrition care. High-protein diet tended to increase insulin resistance and atheromatous risk. Resveratrol improved insulin sensitivity in old mice fed standard diet by decreasing homeostasis model of assessment-insulin resistance and resistin levels. However, resveratrol did not improve insulin resistance status in old mice receiving the high-protein diet. In contrast, resveratrol exhibited deleterious effects by increasing inflammation state and superoxide production and diminishing aortic distensibility. In conclusion, we demonstrate that resveratrol has beneficial or deleterious effects on insulin sensitivity and arterial function, depending on nutritional status in our models.

International audience; Resveratrol (RSV) has been shown to be involved in the regulation of energetic metabolism, generating increasing interest in therapeutic use. SIRT1 has been described as the main target of RSV. However, recent reports have challenged the hypothesis of its direct activation by RSV, and the signaling pathways remain elusive. Here, the effects of RSV on mitochondrial metabolism are detailed both in vivo and in vitro using murine and cellular models and isolated enzymes. We demonstrate that low RSV doses (1-5 muM) directly stimulate NADH dehydrogenases and, more specifically, mitochondrial complex I activity (EC50 approximately 1 muM). In HepG2 cells, this complex I activation increases the mitochondrial NAD(+)/NADH ratio. This higher NAD(+) level initiates a SIRT3-dependent increase in the mitochondrial substrate supply pathways (i.e. the tricarboxylic acid cycle and fatty acid oxidation). This effect is also seen in liver mitochondria of RSV-fed animals (50 mg/kg/day). We conclude that the increase in NADH oxidation by complex I is a crucial event for SIRT3 activation by RSV. Our results open up new perspectives in the understanding of the RSV signaling pathway and highlight the critical importance of RSV doses used for future clinical trials.

Objective— Flow- (shear stress–)mediated outward remodeling of resistance arteries is involved in collateral growth during postischemic revascularization. As this remodeling is especially important during pregnancy, we hypothesized that estrogens may be involved. A surgical model eliciting a local increase in blood flow in 1 mesenteric resistance artery was used in 3-month-old ovariectomized female rats either treated with 17-β-estradiol (E2) or left untreated. Methods and Results— After 14 days, arterial diameter was greater in high-flow arteries than in normal-flow vessels. An ovariectomy suppressed high-flow remodeling, while E2 restored it. High-flow remodeling was absent in mice lacking the estrogen receptor α but not estrogen receptor β. The kinetics of inflammatory marker expression, macrophage infiltration, oxidative stress, and metaloproteinases expression were not altered by the absence of E2 after 2 and 4 days, that is, during remodeling. Nevertheless, E2 was required for the increase in endothelial nitric oxide synthase expression and activation at day 4 when diameter expansion occurs. Finally, the impact of E2 on the endothelium appeared crucial for high-flow remodeling, as this E2 action was abrogated in mice lacking endothelial NOS, as well as in Tie2-Cre(+) ERα f/f mice. Conclusion— We demonstrate the essential role of E2 and endothelial estrogen receptor α in flow-mediated remodeling of resistance arteries in vivo.

Introduction Les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses morbides. Outre la perte de poids, elles reduisent les complications metaboliques frequemment associes, notamment les dyslipidemies. Bien que l'effet hypocholesterolemiant soit dependant de la procedure chirurgicale utilisee, les mecanismes moleculaires impliques demeurent mal definis. Cette etude vise a mesurer les consequences de deux chirurgies bariatriques (la sleeve gastrectomie et le by-pass Roux en Y) sur les voies regulant le metabolisme du cholesterol. Materiels et Methodes Des souris mâles C57BL6/J de 10 semaines ont recu un regime hyperlipidique pendant 8 a 12 semaines avant la chirurgie. Les souris ont ete randomisees sur le poids et la cholesterolemie et reparties dans 3 groupes experimentaux : un groupe sham (laparotomie), un groupe sham « pair-fed » et un groupe « chirurgie ». Nous avons ensuite mesure les consequences des chirurgies sur le poids, la prise alimentaire et le metabolisme glucidique et lipidique. L'analyse des voies d'excretion du cholesterol a ete determinee par spectrometrie de masse (GC-MS). Resultats Deux semaines apres la chirurgie (J +14), la sleeve et le by-pass induisent une reduction du poids corporel (respectivement − 15,63 % et − 25 %, p Conclusions En conclusion, nous avons mis en place deux modeles de chirurgie bariatrique chez la souris. La sleeve a un effet hypocholesterolemiant modeste principalement lie a des modifications du comportement alimentaire, alors que le by-pass induit une reduction importante du cholesterol sanguin en stimulant son excretion fecale.

Introduction En l'absence de traitement pharmacologique, les chirurgies bariatriques representent une alternative therapeutique de choix chez les patients obeses. Outre la perte de poids, les chirurgies bariatriques reduisent efficacement les complications metaboliques de l'obesite, notamment les dyslipidemies. Toutefois, les mecanismes associes demeurent mal connus. Notre etude vise a mesurer les consequences de la sleeve gastrectomie sur le metabolisme intestinal et hepatobiliaire du cholesterol. Materiels et methodes Des souris mâles C57BL6/J âgees de 10 semaines ont recu un regime hyperlipidique 8 semaines avant la chirurgie. Les souris ont ete ensuite randomisees sur le poids et la cholesterolemie et reparties dans 3 groupes experimentaux: un groupe sham (laparotomie), un groupe sham « pair-fed » et un groupe « sleeve ». Le poids, la prise alimentaire, les parametres lipidiques sanguins, l'excretion biliaire, transintestinale (TICE) et fecale de cholesterol ont ete mesurees avant et apres chirurgie. Resultats La duree operatoire moyenne etait de 49,33±5,09 minutes et la mortalite postchirurgicale etait faible: 7,14 % ( n =39). Deux semaines apres la chirurgie, nous avons note une tendance a la reduction de la prise alimentaire chez les souris « sleeve » (-13 % vs souris sham, p =0,08). Les souris « sleeve » presentaient une reduction significative de leur poids (– 8,3 %, p =0,03) et de leur cholesterolemie (– 20 %, p =0,05) par rapport aux souris sham. En revanche, il n'existe pas de difference entre les souris « sleeve » et les souris sham « pair-fed » suggerant que les effets hypocholesterolemiants sont principalement lies a la restriction alimentaire. Conclusion En conclusion, nous avons mis en place avec succes le modele « sleeve » chez la souris. Des analyses plus approfondies (i.e. mesure du TICE) visant a caracteriser l'effet hypocholesterolemiant de le sleeve sont en cours et permettront de determiner s'ils sont independants de la restriction calorique. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.