Aurélie Waget

Unité Inserm U1077, Caen, Lower Normandy, France

Are you Aurélie Waget?

Claim your profile

Publications (40)207.04 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Alterations of the gut microbiota and mucosal barrier are linked with metabolic diseases. Our aim was to investigate the potential benefit of the potential probiotic Bifidobacterium animalis ssp. lactis 420 in reducing high-fat diet-induced body weight gain and diabetes in mice. In the obesity model, C57Bl/6J mice were fed a high-fat diet (60 energy %) for 12 weeks, and gavaged daily with B. lactis 420 (109 cfu) or vehicle. In the diabetes model, mice were fed a high-fat, ketogenic diet (72 energy % fat) for 4 weeks, with a 6-week subsequent treatment with B. lactis 420 (108-1010 cfu/day) or vehicle, after which they were analysed for body composition. We also analysed glucose tolerance, plasma lipopolysaccharide and target tissue inflammation using only one of the B. lactis 420 groups (109 cfu/day). Intestinal bacterial translocation and adhesion were analysed in a separate experiment using an Escherichia coli gavage. Body fat mass was increased in both obese (10.7±0.8 g (mean ± standard error of mean) vs. 1.86±0.21 g, P<0.001) and diabetic mice (3.01±0.4 g vs. 1.14±0.15 g, P<0.001) compared to healthy controls. Treatment with B. lactis 420 significantly decreased fat mass in obese (7.83 ± 0.67 g, P=0.007 compared to obese with vehicle) and diabetic mice (1.89 ± 0.16 g, P=0.02 for highest dose). This was reflected as reduced weight gain and improved glucose tolerance. Furthermore, B. lactis 420 decreased plasma lipopolysaccharide levels (P<0.001), liver inflammation (P=0.04), and E. coli adhesion in the distal gut (P<0.05). In conclusion, B. lactis 420 reduces fat mass and glucose intolerance in both obese and diabetic mice. Reduced intestinal mucosal adherence and plasma lipopolysaccharide suggest a mechanism related to reduced translocation of gut microbes.
    Beneficial Microbes 07/2014; DOI:10.3920/BM2014.0014 · 1.50 Impact Factor
  • Diabetes & Metabolism 03/2014; 40:A69. DOI:10.1016/S1262-3636(14)72464-4 · 2.85 Impact Factor
  • Cahiers de Nutrition et de Diététique 12/2013; 48:S31–S32. DOI:10.1016/S0007-9960(13)70315-8
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Polycystic ovarian syndrome is a common endocrine disorder in females of reproductive age and is believed to have a developmental origin in which gestational androgenization programs reproductive and metabolic abnormalities in offspring. During gestation, both male and female fetuses are exposed to potential androgen excess. We determined the consequences of developmental androgenization in male mice exposed to neonatal testosterone (NTM). Adult NTM displayed hypogonadotropic hypogonadism with decreased serum testosterone and gonadotropins. Hypothalamic KiSS1 neurons are believed to be critical in the onset of puberty and are the target of leptin. Adult NTM showed lower hypothalamic Kiss1 expression and a failure of leptin to upregulate Kiss1 expression. NTM displayed an early reduction in lean mass, decreased locomotor activity and decreased energy expenditure. They developed a delayed increase in subcutaneous white adipose tissue. Thus, excessive neonatal androgenization disrupts reproduction and energy homeostasis and predisposes to hypogonadism and obesity in adult male mice.
    Journal of Endocrinology 10/2013; DOI:10.1530/JOE-13-0230 · 3.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Circulating lipopolysaccharide-binding protein (LBP) is an acute-phase reactant known to be increased in obesity. We hypothesised that LBP is produced by adipose tissue (AT) in association with obesity. LBP mRNA and LBP protein levels were analysed in AT from three cross-sectional (n = 210, n = 144 and n = 28) and three longitudinal (n = 8, n = 25, n = 20) human cohorts; in AT from genetically manipulated mice; in isolated adipocytes; and in human and murine cell lines. The effects of a high-fat diet and exposure to lipopolysaccharide (LPS) and peroxisome proliferator-activated receptor (PPAR)γ agonist were explored. Functional in vitro and ex vivo experiments were also performed. LBP synthesis and release was demonstrated to increase with adipocyte differentiation in human and mouse AT, isolated adipocytes and human and mouse cell lines (Simpson-Golabi-Behmel syndrome [SGBS], human multipotent adipose-derived stem [hMAD] and 3T3-L1 cells). AT LBP expression was robustly associated with inflammatory markers and increased with metabolic deterioration and insulin resistance in two independent cross-sectional human cohorts. AT LBP also increased longitudinally with weight gain and excessive fat accretion in both humans and mice, and decreased with weight loss (in two other independent cohorts), in humans with acquired lipodystrophy, and after ex vivo exposure to PPARγ agonist. Inflammatory agents such as LPS and TNF-α led to increased AT LBP expression in vivo in mice and in vitro, while this effect was prevented in Cd14-knockout mice. Functionally, LBP knockdown using short hairpin (sh)RNA or anti-LBP antibody led to increases in markers of adipogenesis and decreased adipocyte inflammation in human adipocytes. Collectively, these findings suggest that LBP might have an essential role in inflammation- and obesity-associated AT dysfunction.
    Diabetologia 08/2013; DOI:10.1007/s00125-013-3015-9 · 6.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic endotoxemia triggers inflammation, targets cells from the stroma-vascular fraction of adipose depots, and metabolic disease. To identify these cells we here infused mice with lipopolysaccharides and showed by FACS analyses and BrdU staining that the number of small subcutaneous adipocytes, preadipocytes and macrophages increased in wild type but not in CD14-knockout (KO) mice. This mechanism was direct since in CD14KO mice grafted subcutaneously and simultaneously with fat pads from CD14KO and wild-type mice the concentration of cytokine mRNA was increased in the wild-type fat pad only. Conversely, the mRNA concentration of genes involved in glucose and lipid metabolism and the number of large adipocytes was reduced. Eventually, a pretreatment with LPS enhanced HFD-induced metabolic diseases. Altogether, these results show that metabolic endotoxemia increases the proliferation of preadipocytes through a CD14-dependent mechanism directly, without recruiting CD14-positive cells from non-adipose depot origin. This mechanism could precede the onset of metabolic diseases.
    08/2013; 2(3):281-91. DOI:10.1016/j.molmet.2013.06.005
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The beneficial metabolic actions of estrogen-based therapies are mainly mediated by estrogen receptor-α (ERα), a nuclear receptor which regulates gene transcription through two activation functions (AFs), AF-1 and AF-2. Using mouse models deleted electively for ERαAF-1 (ERαAF-1(0)) or ERαAF-2 (ERαAF-2(0)), we determined their respective roles in the actions of estrogens on body composition and glucose homeostasis, either under normal diet or in response to a high-fat diet. ERαAF-2(0) males and females developed accelerated weight gain, massive adiposity, severe insulin resistance and glucose intolerance, quite reminiscent to the phenotype observed in mice deleted for the entire ERα protein (ERα(-/-)). In striking contrast, ERαAF-1(0) and wild-type mice shared a similar metabolic phenotype. Accordingly, 17β-estradiol administration regulated key metabolic genes in insulin-sensitive tissues and conferred a strong protection against high-fat diet-induced metabolic disturbances in wild-type and ERαAF-1(0) ovariectomized mice, while these actions were totally abrogated in ERαAF-2(0) and ERα(-/-) mice. Thus, whereas both AFs have been previously shown to contribute to endometrial and breast cancer cell proliferation, the protective effect of estrogens against obesity and insulin resistance depends on ERαAF-2 but not on ERαAF-1, thereby delineating new options for selective modulation of ERα.
    Diabetes 07/2013; 62(12). DOI:10.2337/db13-0282 · 8.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Among women, the polycystic ovarian syndrome (PCOS) is considered a form of metabolic syndrome with reproductive abnormalities. Women with PCOS show increased sympathetic tone, visceral adiposity with enlarged adipocytes, hypoadiponectinemia, insulin resistance, glucose intolerance, increased inactive osteocalcin and hypertension. Excess fetal exposure to androgens has been hypothesized to play a role in the pathogenesis of PCOS. Previously, we showed that neonatal exposure to the androgen testosterone (NT) programs leptin resistance in adult female mice. Here, we studied the impact of NT on lean and adipose tissues, sympathetic tone in cardiometabolic tissues and the development of metabolic dysfunction in mice. Neonatally androgenized adult female mice (NTF) displayed masculinization of lean tissues with increased cardiac and skeletal muscle as well as kidney masses. NTF mice showed increased and dysfunctional white adipose tissue with increased sympathetic tone in both visceral and subcutaneous fat, as well as increased number of enlarged and insulin resistant adipocytes that displayed altered expression of developmental genes and hypoadiponectinemia. NTF exhibited dysfunctional brown adipose tissue with increased mass and decreased energy expenditure. They also displayed decreased undercarboxylated and active osteocalcin and were predisposed to obesity during chronic androgen excess. NTF showed increased renal sympathetic tone associated with increased blood pressure and they developed glucose intolerance and insulin resistance. Thus, developmental exposure to testosterone in female mice programs features of cardiometabolic dysfunction as can be observed in women with PCOS including increased sympathetic tone, visceral adiposity, insulin resistance, pre-diabetes and hypertension.
    AJP Endocrinology and Metabolism 04/2013; 304(12). DOI:10.1152/ajpendo.00620.2012 · 4.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.
    PLoS Biology 02/2013; 11(2):e1001485. DOI:10.1371/journal.pbio.1001485 · 11.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lactoferrin is considered an epithelial protein present in different gland secretions. Administration of exogenous lactoferrin is also known to modulate adipogenesis and insulin action in human adipocytes. Here, we aimed to investigate lactoferrin gene expression (real-time polymerase chain reaction) and protein (enzyme-linked immunosorbent assay) levels in human (n=143) and mice adipose tissue samples, in adipose tissue fractions and during human preadipocyte and 3T3-L1 cell line differentiation, evaluating the effects of inducers (rosiglitazone) and disruptors (inflammatory factors) of adipocyte differentiation. Lactoferrin (LTF) gene and protein were detectable at relatively high levels in whole adipose tissue and isolated adipocytes in direct association with low-density lipoprotein-related protein 1 (LRP1, its putative receptor). Obese subjects with type 2 diabetes and increased triglycerides had the lowest levels of LTF gene expression in subcutaneous adipose tissue. Specifically, LTF gene expression was significantly increased in adipocytes, mainly from lean subjects, increasing during differentiation in parallel to adipogenic genes and gene markers of lipid droplets. The induction or disruption of adipogenesis led to concomitant changes (increase and decrease, respectively) of lactoferrin levels during adipocyte differentiation also in parallel to gene markers of adipogenesis and lipid droplet development. The administration of lactoferrin led to autopotentiated increased expression of the LTF gene. The decreased lactoferrin mRNA levels in association with obesity and diabetes were replicated in mice adipose tissue. In conclusion, this is the first observation, to our knowledge, of lactoferrin gene expression in whole adipose tissue and isolated adipocytes, increasing during adipogenesis and suggesting a possible contribution in adipose tissue physiology through LRP1.
    The Journal of nutritional biochemistry 01/2013; DOI:10.1016/j.jnutbio.2012.10.002 · 4.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance. Metabolic studies were performed in Chop ( -/- ) and wild-type C57Bl/6 mice, and included euglycaemic-hyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop ( -/- ) mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance.
    Diabetologia 04/2012; 55(4):1167-78. DOI:10.1007/s00125-011-2427-7 · 6.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondria are dynamic organelles that play a key role in energy conversion. Optimal mitochondrial function is ensured by a quality-control system tightly coupled to fusion and fission. In this connection, mitofusin 2 (Mfn2) participates in mitochondrial fusion and undergoes repression in muscle from obese or type 2 diabetic patients. Here, we provide in vivo evidence that Mfn2 plays an essential role in metabolic homeostasis. Liver-specific ablation of Mfn2 in mice led to numerous metabolic abnormalities, characterized by glucose intolerance and enhanced hepatic gluconeogenesis. Mfn2 deficiency impaired insulin signaling in liver and muscle. Furthermore, Mfn2 deficiency was associated with endoplasmic reticulum stress, enhanced hydrogen peroxide concentration, altered reactive oxygen species handling, and active JNK. Chemical chaperones or the antioxidant N-acetylcysteine ameliorated glucose tolerance and insulin signaling in liver-specific Mfn2 KO mice. This study provides an important description of a unique unexpected role of Mfn2 coordinating mitochondria and endoplasmic reticulum function, leading to modulation of insulin signaling and glucose homeostasis in vivo.
    Proceedings of the National Academy of Sciences 03/2012; 109(14):5523-8. DOI:10.1073/pnas.1108220109 · 9.81 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF). We evaluated the impact of either a 2 month pharmacological inhibition, or a gene deletion of PTP1B (PTP1B(-/-)) in CHF mice (2 months post-myocardial infarction). PTP1Bi and PTP1B deficiency reduced adverse LV remodeling, and improved LV function, as shown by the increased LV fractional shortening and cardiac output (measured by echocardiography), the increased LV end systolic pressure, and the decreased LV end diastolic pressure, at identical infarct sizes. This was accompanied by reduced cardiac fibrosis, myocyte hypertrophy and cardiac expression of ANP. In vitro vascular studies performed in small mesenteric artery segments showed a restored endothelial function (i.e. improved NO-dependent, flow-mediated dilatation, increased eNOS phosphorylation) after either pharmacological inhibition or gene deletion. PTP1B(-/-) CHF also displayed an improved insulin sensitivity (assessed by euglycemic-hyperinsulinemic clamp studies), when compared to wild-type CHF associated with an increased insulin mediated mesenteric artery dilation. Thus, chronic pharmacological inhibition or gene deletion of PTP1B improves cardiac dysfunction and cardiac remodeling in the absence of changes in infarct size. Thus this enzyme may be a new therapeutic target in CHF. Diabetic patients with cardiac complications may potentially benefit from PTP1B inhibition via two different mechanisms, reduced diabetic complications, and reduced heart failure.
    Journal of Molecular and Cellular Cardiology 03/2012; 52(6):1257-64. DOI:10.1016/j.yjmcc.2012.03.003 · 5.22 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction La maladie parodontale (MP) est définie comme une maladie infectieuse bactérienne bucco-dentaire multifactorielle à manifestation inflammatoire locale à bas bruit. Or, une des principales causes de l’insulinorésistance chez les diabétiques est la réaction inflammatoire métabolique. Des données récentes de la littérature démontrent le rôle causal de la flore intestinale dans l’induction de l’inflammation métabolique. Ainsi, nous suggérons que l’infection buccale caractérisant la MP puisse être considérée comme un facteur de risque initiant ou aggravant l’inflammation et ainsi l’insulinorésistance et le développement du diabète de type 2. Matériels et méthodes Nous avons identifié par RT-PCR qu’un régime gras induisait un changement de flore buccale qui correspondait à une augmentation de la proportion de Prevotella intermedia et Fusobacterium nucleatum dans le microbiote parodontal. Pour évaluer l’impact de ces bactéries parodonto-pathogènes en tant que facteur de risque du diabète, des souris ont initialement été colonisées par cette microflore sous-gingivale pathogène puis après un mois nourries avec un régime normal (NCD) ou riche en lipides diabétogène (HFD) et affiliées dans quatre groupes: NCD (n = 6), NCD + MP (n = 6), HFD (n = 19) et HFD + MP (n = 17). Le phénotype diabétique a été évalué en effectuant un test de tolérance oral au glucose et un clamp hyperinsulinémique euglycémique. La lyse osseuse alvéolaire mandibulaire a été évaluée par tomodensitométrie et les cytokines inflammatoires du foie, du tissu adipeux, du muscle et du tissu parodontal ont été quantifiées par RT-PCR. La pression artérielle fut mesurée à la queue à l’aide du système CODA®. Résultats La colonisation bactérienne a induit une lyse osseuse mandibulaire (p < 0, 0001) ce qui caractérise l’induction d’une MP. La MP amplifie la pression systolique chez les souris diabétiques (p = 0,021). La résistance à l’insuline induite par le régime gras était majorée par l’infection du tissu parodontal. Cette observation suggérait que la MP représentait un facteur de risque du développement du diabète car la résorption osseuse alvéolaire est corrélée avec la tolérance au glucose, la sensibilité à l’insuline (p = 0, 037), et l’hypertension artérielle, par rapport aux souris témoins. Conclusion Ainsi, la modification du microbiote parodontal associée à l’inflammation du parodonte peut être considérée comme un facteur de risque de déséquilibre de l’homéostasie du glucose et plus largement du syndrome métabolique. Nos résultats montrent que l’état parodontal peut représenter un nouvel axe de traitement des maladies métaboliques.
    Diabetes & Metabolism 03/2012; 38:A9. DOI:10.1016/S1262-3636(12)71013-3 · 2.85 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective:Lipopolysaccharide-binding protein (LBP) is a 65-kDa acute-phase protein present in blood at high concentrations, known to be derived from the liver. We aimed to gain insights into the association of circulating LBP with insulin resistance in humans and mice.Methods, design and measurements:We studied the cross-sectional (n=222) and weight loss-induced (n=34) associations of LBP (enzyme-linked immunosorbent assay) with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity), and the effects of high-fat diet (HFD), metformin and genetic insulin sensitization (glucagon-like peptide 1 receptor knockout model) in mice.Results:Circulating LBP concentration was significantly increased in subjects with type 2 diabetes and dramatically increased in subjects with morbid obesity. LBP was significantly associated with insulin sensitivity and different inflammatory markers and decreased after weight loss (22.2±5.8 vs 16.2±9.3 μg ml(-1), P<0.0001) in association with changes in body mass index and insulin sensitivity. Circulating LBP concentration was increased in HFD mice, whereas decreased in glucagon-like peptide 1 receptor knockout mice (significantly more insulin sensitive than wild-type mice) and after metformin administration.Conclusion:LBP is an inflammatory marker associated with obesity-related insulin resistance.International Journal of Obesity advance online publication, 20 December 2011; doi:10.1038/ijo.2011.256.
    International journal of obesity (2005) 12/2011; 36(11). DOI:10.1038/ijo.2011.256 · 5.39 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The gut microbiota, which is considered a causal factor in metabolic diseases as shown best in animals, is under the dual influence of the host genome and nutritional environment. This study investigated whether the gut microbiota per se, aside from changes in genetic background and diet, could sign different metabolic phenotypes in mice. The unique animal model of metabolic adaptation was used, whereby C57Bl/6 male mice fed a high-fat carbohydrate-free diet (HFD) became either diabetic (HFD diabetic, HFD-D) or resisted diabetes (HFD diabetes-resistant, HFD-DR). Pyrosequencing of the gut microbiota was carried out to profile the gut microbial community of different metabolic phenotypes. Inflammation, gut permeability, features of white adipose tissue, liver and skeletal muscle were studied. Furthermore, to modify the gut microbiota directly, an additional group of mice was given a gluco-oligosaccharide (GOS)-supplemented HFD (HFD+GOS). Despite the mice having the same genetic background and nutritional status, a gut microbial profile specific to each metabolic phenotype was identified. The HFD-D gut microbial profile was associated with increased gut permeability linked to increased endotoxaemia and to a dramatic increase in cell number in the stroma vascular fraction from visceral white adipose tissue. Most of the physiological characteristics of the HFD-fed mice were modulated when gut microbiota was intentionally modified by GOS dietary fibres. The gut microbiota is a signature of the metabolic phenotypes independent of differences in host genetic background and diet.
    Gut 11/2011; 61(4):543-53. DOI:10.1136/gutjnl-2011-301012 · 13.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A fat-enriched diet modifies intestinal microbiota and initiates a low-grade inflammation, insulin resistance and type-2 diabetes. Here, we demonstrate that before the onset of diabetes, after only one week of a high-fat diet (HFD), live commensal intestinal bacteria are present in large numbers in the adipose tissue and the blood where they can induce inflammation. This translocation is prevented in mice lacking the microbial pattern recognition receptors Nod1 or CD14, but overtly increased in Myd88 knockout and ob/ob mouse. This ‘metabolic bacteremia’ is characterized by an increased co-localization with dendritic cells from the intestinal lamina propria and by an augmented intestinal mucosal adherence of non-pathogenic Escherichia coli. The bacterial translocation process from intestine towards tissue can be reversed by six weeks of treatment with the probiotic strain Bifidobacterium animalis subsp. lactis 420, which improves the animals' overall inflammatory and metabolic status. Altogether, these data demonstrate that the early onset of HFD-induced hyperglycemia is characterized by an increased bacterial translocation from intestine towards tissues, fuelling a continuous metabolic bacteremia, which could represent new therapeutic targets.
    EMBO Molecular Medicine 09/2011; 3(9):559 - 572. DOI:10.1002/emmm.201100159 · 8.25 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The study objective was to evaluate the possible role of the macrophage molecule CD14 in insulin resistance. The effects of recombinant human soluble CD14 (rh-sCD14) on insulin sensitivity (clamp procedure) and adipose tissue gene expression were evaluated in wild-type (WT) mice, high fat-fed mice, ob/ob mice, and CD14 knockout (KO) mice. We also studied WT mice grafted with bone marrow stem cells from WT donor mice and CD14 KO mice. Finally, CD14 was evaluated in human adipose tissue and during differentiation of human preadipocytes. rh-sCD14 led to increased insulin action in WT mice, high-fat-fed mice, and ob/ob mice, but not in CD14 KO mice, in parallel to a marked change in the expression of 3,479 genes in adipose tissue. The changes in gene families related to lipid metabolism were most remarkable. WT mice grafted with bone marrow stem cells from WT donor mice became insulin resistant after a high-fat diet. Conversely, WT mice grafted with cells from CD14 KO mice resisted the occurrence of insulin resistance in parallel to decreased mesenteric adipose tissue inflammatory gene expression. Glucose intolerance did not worsen in CD14 KO mice grafted with bone marrow stem cells from high fat-fed WT mice when compared with recipient KO mice grafted with cells from CD14 KO donor mice. CD14 gene expression was increased in whole adipose tissue and adipocytes from obese humans and further increased after tumor necrosis factor-α. CD14 modulates adipose tissue inflammatory activity and insulin resistance.
    Diabetes 06/2011; 60(8):2179-86. DOI:10.2337/db10-1210 · 8.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Daily variations in lipid concentrations in both gut lumen and blood are detected by specific sensors located in the gastrointestinal tract and in specialized central areas. Deregulation of the lipid sensors could be partly involved in the dysfunction of glucose homeostasis. The study aimed at comparing the effect of Medialipid (ML) overload on insulin secretion and sensitivity when administered either through the intestine or the carotid artery in mice. An indwelling intragastric or intracarotid catheter was installed in mice and ML or an isocaloric solution was infused over 24 hours. Glucose and insulin tolerance and vagus nerve activity were assessed. Some mice were treated daily for one week with the anti-lipid peroxidation agent aminoguanidine prior to the infusions and tests. The intestinal but not the intracarotid infusion of ML led to glucose and insulin intolerance when compared with controls. The intestinal ML overload induced lipid accumulation and increased lipid peroxidation as assessed by increased malondialdehyde production within both jejunum and duodenum. These effects were associated with the concomitant deregulation of vagus nerve. Administration of aminoguanidine protected against the effects of lipid overload and normalized glucose homeostasis and vagus nerve activity. Lipid overload within the intestine led to deregulation of gastrointestinal lipid sensing that in turn impaired glucose homeostasis through changes in autonomic nervous system activity.
    PLoS ONE 06/2011; 6(6):e21184. DOI:10.1371/journal.pone.0021184 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Inhibition of dipeptidyl peptidase-4 (DPP-4) activity improves glucose homeostasis through a mode of action related to the stabilization of the active forms of DPP-4-sensitive hormones such as the incretins that enhance glucose-induced insulin secretion. However, the DPP-4 enzyme is highly expressed on the surface of intestinal epithelial cells; hence, the role of intestinal vs. systemic DPP-4 remains unclear. To analyze mechanisms through which the DPP-4 inhibitor sitagliptin regulates glycemia in mice, we administered low oral doses of the DPP-4 inhibitor sitagliptin that selectively reduced DPP-4 activity in the intestine. Glp1r(-/-) and Gipr(-/-) mice were studied and glucagon-like peptide (GLP)-1 receptor (GLP-1R) signaling was blocked by an i.v. infusion of the corresponding receptor antagonist exendin (9-39). The role of the dipeptides His-Ala and Tyr-Ala as DPP-4-generated GLP-1 and glucose-dependent insulinotropic peptide (GIP) degradation products was studied in vivo and in vitro on isolated islets. We demonstrate that very low doses of oral sitagliptin improve glucose tolerance and plasma insulin levels with selective reduction of intestinal but not systemic DPP-4 activity. The glucoregulatory action of sitagliptin was associated with increased vagus nerve activity and was diminished in wild-type mice treated with the GLP-1R antagonist exendin (9-39) and in Glp1r(-/-) and Gipr(-/-) mice. Furthermore, the dipeptides liberated from GLP-1 (His-Ala) and GIP (Tyr-Ala) deteriorated glucose tolerance, reduced insulin, and increased portal glucagon levels. The predominant mechanism through which DPP-4 inhibitors regulate glycemia involves local inhibition of intestinal DPP-4 activity, activation of incretin receptors, reduced liberation of bioactive dipeptides, and activation of the gut-to-pancreas neural axis.
    Endocrinology 06/2011; 152(8):3018-29. DOI:10.1210/en.2011-0286 · 4.64 Impact Factor

Publication Stats

3k Citations
207.04 Total Impact Points

Institutions

  • 2013
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Xiamen University
      Amoy, Fujian, China
  • 2009–2013
    • University of Toulouse
      Tolosa de Llenguadoc, Midi-Pyrénées, France
  • 2008–2013
    • French Institute of Health and Medical Research
      • Institute of Metabolic and Cardiovascular Diseases I2MC
      Lutetia Parisorum, Île-de-France, France
    • Catholic University of Louvain
      • Institute of Experimental and Clinical Research (IREC)
      Walloon Region, Belgium
  • 2006–2013
    • Paul Sabatier University - Toulouse III
      • Institut des Maladies Métaboliques et Cardiovasculaires de Toulouse - UMRS 1048 - I2MC
      Tolosa de Llenguadoc, Midi-Pyrénées, France
    • University of Lausanne
      Lausanne, Vaud, Switzerland
  • 2007
    • University of Reading
      Reading, England, United Kingdom
  • 2005
    • Centre de Recherche Pierre Fabre
      Tolosa de Llenguadoc, Midi-Pyrénées, France