Communication inter-organes dans le contrôle du métabolisme glucidique : mise en évidence de l'implication du monoxyde d'azote et de l'apeline dans l'hypothalamus

L'hypothalamus est une structure du système nerveux central fortement impliquée dans la régulation de l'homéostasie glucidique. En effet, il reçoit en permanence des signaux d'origines diverses (nerveuses, endocriniennes, ou même métaboliques) en provenance d'un grand nombre d'organes périphériques qui l'informent sur l'état métabolique global de l'organisme. L'intégration de ces informations aboutit à l'élaboration d'une réponse nerveuse adaptée qui sera envoyée en périphérie via le système nerveux autonome et modulera en retour l'activité des organes périphériques afin de maintenir la glycémie dans des limites strictes. Dès lors, un dysfonctionnement dans cette boucle de régulation peut participer à l'établissement de maladies métaboliques telles que l'obésité ou le diabète de type II. Au cours de ce doctorat, nous nous sommes attachés à identifier de nouveaux mécanismes et acteurs moléculaires impliqués dans ces communications entre la périphérie et l'hypothalamus dans des conditions physiologiques et physiopathologiques. Dans une première étude, nous avons pu montrer que l'inflammation et le stress du réticulum endoplasmique observés au niveau du jéjunum d'animaux obèses modifie la libération hypothalamique de monoxyde d'azote (NO) en réponse à la détection entérique de glucose. Dès lors, nous montrons que les senseurs entériques au glucose peuvent être considérés comme des cibles thérapeutiques potentielles pour les maladies métaboliques. Dans une seconde étude, nous avons plus particulièrement étudié les effets centraux de l'apeline, peptide bioactif original du fait de sa double origine puisqu'il est produit par le tissu adipeux mais également au niveau hypothalamique. Nos résultats montrent que le NO hypothalamique est nécessaire à l'établissement de certains effets bénéfiques périphériques de l'apeline sur l'homéostasie glucidique (diminution de la glycémie nourrie, amélioration de la tolérance au glucose). Par ailleurs, nous avons également démontré que les effets centraux de l'apeline dépendaient de la dose injectée, de la situation énergétique (à jeun/nourri) et de la situation métabolique (maigre/obèse) de l'organisme. Ainsi, de forts taux d'apeline hypothalamique participent à la mise en place d'un diabète de type 2. L'ensemble de ces travaux de doctorat renforce l'importance des communications inter-organes dans le contrôle de l'homéostasie glucidique, et propose de nouvelles cibles moléculaires (apeline) et tissulaires (intestin) pour le traitement du diabète de type 2.The hypothalamus is a central nervous system area which is strongly involved in the control of glucose homeostasis. Indeed, the hypothalamus is able to detect peripheral signals from various organs which inform the body about the nutritional/metabolic state. These signals are from various origins (nervous, endocrine or metabolic) and modifications of the hypothalamic neuronal activity modulated by these factors generate an adaptive nervous signal which will be send to periphery via the autonomous nervous system (ANS). In response to the activation of ANS, peripheral organs create an appropriate response in order to maintain blood glucose in physiological state. Once, dysfunction in this regulating loop can be implicated in the development of metabolic disease such as obesity or type 2 diabetes. During this PhD, we aimed at identifying new mechanisms and molecular actors involved in these communications between peripheral tissue and hypothalamus under physiological and pathological state. First, we demonstrate that inflammation and endoplasmic reticulum stress that occur in the jejunum of obese animals can modify the hypothalamic release of nitric oxide (NO) in response to stimulation of enteric glucose sensors. Our data strongly reinforce the hypothesis that the "gut-to-brain" axis can be now considered as new potential therapeutic targets for treatment of metabolic disease. In a second study, we focused our intention of central effects of apelin, a bioactive peptide produced by adipose tissue and hypothalamic neurons. Our results show that hypothalamic NO is implicated in the establishment of beneficial peripheral effects of central apelin on glucose homeostasis (decrease fed glycemia, increase glucose tolerance). In another hand, we also demonstrate that central effects of apelin were strongly dependant of the injected dose, the nutritional state (fasted/fed) and the metabolic state (lean/obese). Thus, high dose of hypothalamic apelin participate to the development of type 2 diabetes. This work reinforces the importance of inter-organs communications in the control of glucose homeostasis and offers new molecular (apelin) and tissular (gut) targets for the treatment of type 2 diabetes

Fecal Enterobacteriales enrichment is associated with increased in vivo intestinal permeability in humans

Type 2 diabetes (T2D) has been linked with increased intestinal permeability, but the clinical significance of this phenomenon remains unknown. The objective of this study was to investigate the potential link between glucose control, intestinal permeability, diet and intestinal microbiota in patients with T2D. Thirty‐two males with well‐controlled T2D and 30 age‐matched male controls without diabetes were enrolled in a case–control study. Metabolic parameters, inflammatory markers, endotoxemia, and intestinal microbiota in individuals subdivided into high (HP) and normal (LP) colonic permeability groups, were the main outcomes. In T2D, the HP group had significantly higher fasting glucose (P = 0.034) and plasma nonesterified fatty acid levels (P = 0.049) compared with the LP group. Increased colonic permeability was also linked with altered abundances of selected microbial taxa. The microbiota of both T2D and control HP groups was enriched with Enterobacteriales. In conclusion, high intestinal permeability was associated with poorer fasting glucose control in T2D patients and changes in some microbial taxa in both T2D patients and nondiabetic controls. Therefore, enrichment in the gram‐negative order Enterobacteriales may characterize impaired colonic permeability prior to/independently from a disruption in glucose tolerance

Host-microbiome interactionsin human type 2 diabetes following prebiotic fibre (galactooligosaccharide) intake

Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r −0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes

Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism

OBJECTIVE: To examine the role of hepatocyte myeloid differentiation primary-response gene 88 (MyD88) on glucose and lipid metabolism. DESIGN: To study the impact of the innate immune system at the level of the hepatocyte and metabolism, we generated mice harbouring hepatocyte-specific deletion of MyD88. We investigated the impact of the deletion on metabolism by feeding mice with a normal control diet or a high-fat diet for 8 weeks. We evaluated body weight, fat mass gain (using time-domain nuclear magnetic resonance), glucose metabolism and energy homeostasis (using metabolic chambers). We performed microarrays and quantitative PCRs in the liver. In addition, we investigated the gut microbiota composition, bile acid profile and both liver and plasma metabolome. We analysed the expression pattern of genes in the liver of obese humans developing non-alcoholic steatohepatitis (NASH). RESULTS: Hepatocyte-specific deletion of MyD88 predisposes to glucose intolerance, inflammation and hepatic insulin resistance independently of body weight and adiposity. These phenotypic differences were partially attributed to differences in gene expression, transcriptional factor activity (ie, peroxisome proliferator activator receptor-α, farnesoid X receptor (FXR), liver X receptors and STAT3) and bile acid profiles involved in glucose, lipid metabolism and inflammation. In addition to these alterations, the genetic deletion of MyD88 in hepatocytes changes the gut microbiota composition and their metabolomes, resembling those observed during diet-induced obesity. Finally, obese humans with NASH displayed a decreased expression of different cytochromes P450 involved in bioactive lipid synthesis. CONCLUSIONS: Our study identifies a new link between innate immunity and hepatic synthesis of bile acids and bioactive lipids. This dialogue appears to be involved in the susceptibility to alterations associated with obesity such as type 2 diabetes and NASH, both in mice and humans

Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study

Background Epidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C. Method Serum IF1 levels were measured in 577 male participants with stable CAD (age 45–74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths. Results IF1 levels were positively correlated with HDL-C (rs = 0.40; P < 0.001) and negatively with triglycerides (rs = −0.21, P < 0.001) and CAD severity documented by the Gensini score (rs = −0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38–0.89 and 0.50 (0.28–0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02). Conclusions We investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy

Étude géotechnique de l'extension d'une station de métro existante, avec ouvrages géothermiques

La Société du Métro de l'Agglomération Toulousaine (SMAT) prévoit d'améliorer la capacité de la ligne A. Les stations de cette ligne de métro automatique peuvent actuellement accueillir des compositions de deux rames accouplées. L'objectif est d'exploiter la ligne avec des compositions de 4 rames, d'une longueur totale de 52 m. La station Fontaine l'Estang, réalisée à l'intérieur d'une enceinte en parois moulées, doit donc être étendue de 26 m. Cette extension implique de terrasser autour du tunnel existant du métro. L'objectif du projet est de définir la solution optimale pour l'enceinte de fouille et son étayage permettant de respecter les contraintes de déformation des avoisinants. Les études prendront en considération l'interaction sol-structure, ainsi que les méthodes et le phasage des travaux. L'intégration de structures géothermiques dans les nouvelles structures de la station est prévue

Gut microbiota, enteroendocrine functions and metabolism

The gut microbiota affects host metabolism through a number of physiological processes. Emerging evidence suggests that gut microbes interact with the host through several pathways involving enteroendocrine cells (e.g. L cells). The activation of specific G protein coupled receptors expressed on L cells (e.g. GPR41, GPR43, GPR119 and TGR5) triggers the secretion of glucagon-like peptides (GLP-1 and GLP-2) and PYY. These gut peptides are known to control energy homeostasis, glucose metabolism, gut barrier function and metabolic inflammation. Here, we explore how crosstalk between the ligands produced by the gut microbiota (short chain fatty acids, or SCFAs), or produced by the host but influenced by gut microbes (endocannabinoids and bile acids), impact host physiology

Hypothalamic actions of apelin on energy metabolism: New insight on glucose homeostasis and metabolic disorders

Hypothalamus is key area implicated in control of glucose homeostasis. This structure integrates nervous and peripheral informations to adapt a response modifying peripheral glucose utilization and maintaining energetic balance. Among peripheral signals, adipokines such as adiponectin and leptin are of special importance since deregulations of their actions are closely associated to metabolic disorders such as obesity and type 2 diabetes. During the past ten years, we have identified a new adipokine named apelin which has emerging role in the control of metabolism. The originality of the apelinergic system is to be largely represented in peripheral tissues (adipose tissue, intestine, etc.) and in the brain. Then, apelin is released by adipose tissue as all adipokines, but also present another crucial role as neurotransmitter in hypothalamic neurons. By acting in the whole body, apelin exerts pleiotropic actions and is now considered as a major determinant of physiological functions. Besides its general beneficial effects on peripheral targets, central action of apelin remains still a matter of debate. In this review, we have made a parallel between peripheral vs. central actions of apelin in term of signalization and effects. Then, we have focused our attention on hypothalamic apelin and its potential role in glucose metabolism and associated pathologies. © 2013 Georg Thieme Verlag KG Stuttgart New York

Glucose metabolism: focus on gut microbiota, the endocannabinoid system and beyond.

The gut microbiota is now considered as a key factor in the regulation of numerous metabolic pathways. Growing evidence suggests that cross-talk between gut bacteria and host is achieved through specific metabolites (such as short-chain fatty acids) and molecular patterns of microbial membranes (lipopolysaccharides) that activate host cell receptors (such as toll-like receptors and G-protein-coupled receptors). The endocannabinoid (eCB) system is an important target in the context of obesity, type 2 diabetes (T2D) and inflammation. It has been demonstrated that eCB system activity is involved in the control of glucose and energy metabolism, and can be tuned up or down by specific gut microbes (for example, Akkermansia muciniphila). Numerous studies have also shown that the composition of the gut microbiota differs between obese and/or T2D individuals and those who are lean and non-diabetic. Although some shared taxa are often cited, there is still no clear consensus on the precise microbial composition that triggers metabolic disorders, and causality between specific microbes and the development of such diseases is yet to be proven in humans. Nevertheless, gastric bypass is most likely the most efficient procedure for reducing body weight and treating T2D. Interestingly, several reports have shown that the gut microbiota is profoundly affected by the procedure. It has been suggested that the consistent postoperative increase in certain bacterial groups such as Proteobacteria, Bacteroidetes and Verrucomicrobia (A. muciniphila) may explain its beneficial impact in gnotobiotic mice. Taken together, these data suggest that specific gut microbes modulate important host biological systems that contribute to the control of energy homoeostasis, glucose metabolism and inflammation in obesity and T2D