New insights into the inter-organ crosstalk mediated by ChREBP

Carbohydrate response element binding protein (ChREBP) is a glucose responsive transcription factor recognized by its critical role in the transcriptional control of glycolysis and de novo lipogenesis. Substantial advances in the field have revealed novel ChREBP functions. Indeed, due to its actions in different tissues, ChREBP modulates the inter-organ communication through secretion of peptides and lipid factors, ensuring metabolic homeostasis. Dysregulation of these orchestrated interactions is associated with development of metabolic diseases such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD). Here, we recapitulate the current knowledge about ChREBP-mediated inter-organ crosstalk through secreted factors and its physiological implications. As the liver is considered a crucial endocrine organ, we will focus in this review on the role of ChREBP-regulated hepatokines. Lastly, we will discuss the involvement of ChREBP in the progression of metabolic pathologies, as well as how the impairment of ChREBP-dependent signaling factors contributes to the onset of such diseases

Obesity promotes fumonisin B1 hepatotoxicity

Obesity, which is a worldwide public health issue, is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by the Fusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. We investigated whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity. Thus, metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. Mice received a high-fat diet (HFD) or normal chow diet (CHOW) for 15 weeks. Then, during the last three weeks, mice were exposed to these diets in combination or not with FB1 (10 mg/kg body weight/day) through drinking water. As expected, HFD feeding induced significant body weight gain, increased fasting glycemia, and hepatic steatosis. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes. These results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.L.D. PhD was supported by the INRAE Animal Health department. This work was also supported by grants from the French National Research Agency (ANR) Fumolip (ANR-16-CE21-0003) and the Hepatomics FEDER program of Région Occitanie. We thank Prof Wentzel C. Gelderblom for generously providing the FB1 and for his interest and support in our project. B.C. laboratory is supported by a Starting Grant from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement No. ERC-2018-StG- 804135), a Chaire d'Excellence from IdEx Université de Paris - ANR-18-IDEX-0001, an Innovator Award from the Kenneth Rainin Foundation, an ANR grant EMULBIONT ANR-21-CE15-0042-01 and the national program “Microbiote” from INSERM. We thank Anexplo (Genotoul, Toulouse) for their excellent work on plasma biochemistry. Neutral Lipids MS and NMR experiments were performed with instruments in the Metatoul-AXIOM platform. Sphingolipid MS analysis were performed with instruments in the RUBAM platform. The FB1 plasma levels were determined using an UPLC-MS/MS instrument part of the Ghent University MSsmall expertise centre for advanced mass spectrometry analysis of small organic molecules. We thank Elodie Rousseau-Bacquié and all members of the EZOP staff for their assistance in the animal facility. We are very grateful to Talal al Saati for histology analyses and review, and we thank all members of the US006/CREFRE staff at the histology facility and the Genom'IC platforms (INSERM U1016, Paris, France) for their expertise.Peer reviewe

Rhubarb Supplementation Prevents Diet-Induced Obesity and Diabetes in Association with Increased Akkermansia muciniphila in Mice

Obesity and obesity-related disorders, such as type 2 diabetes have been progressively increasing worldwide and treatments have failed to counteract their progression. Growing evidence have demonstrated that gut microbiota is associated with the incidence of these pathologies. Hence, the identification of new nutritional compounds, able to improve health through a modulation of gut microbiota, is gaining interest. In this context, the aim of this study was to investigate the gut-driving effects of rhubarb extract in a context of diet-induced obesity and diabetes. Eight weeks old C57BL6/J male mice were fed a control diet (CTRL), a high fat and high sucrose diet (HFHS) or a HFHS diet supplemented with 0.3% (g/g) of rhubarb extract for eight weeks. Rhubarb supplementation fully prevented HFHS-induced obesity, diabetes, visceral adiposity, adipose tissue inflammation and liver triglyceride accumulation, without any modification in food intake. By combining sequencing and qPCR methods, we found that all these effects were associated with a blooming of Akkermansia muciniphila, which is strongly correlated with increased expression of Reg3γ in the colon. Our data showed that rhubarb supplementation is sufficient to protect against metabolic disorders induced by a diet rich in lipid and carbohydrates in association with a reciprocal interaction between Akkermansia muciniphila and Reg3γ

Homéostasie des céramides et hépatopathies métaboliques

Prevalence of obesity and type II diabetes is constantly increasing in industrialized countries. NAFLD (" Non-Alcoholic Fatty Liver Disease ") is the hepatic manifestation of these pathologies. NAFLD represents a significant public health problem and is defined as a nexus of metabolic and hepatic diseases. NAFLD begins with fatty accumulation in the liver named "hepatic steatosis". Lipids can accumulate in different forms like triglycerides, cholesterol esters, diglycerides and ceramides. Lipotoxicity induced by the accumulation of these lipid species leads to cellular dysfunction and insulin resistance. In this context, we studied the role of ceramides in apparition and evolution of NAFLD in vivo. For this purpose, we used pharmacological, genetic and nutritional approaches. By pharmacological approach, we showed that fumonisin b1, a mycotoxin targeting ceramide synthesis, leads to hepatic toxicity, which is dependent from LXR ("Liver X Receptor"), a major transcriptional regulator of lipid metabolism. Then, we combined genetic and nutritional approaches in order to induce or protect from hepatic steatosis. For this, we used mice with hepatic or total deletion for PPARa (" Peroxisome Proliferator-Activated Receptor alpha "), a transcriptional factor essential in fatty acid catabolism. First, this model allow us to confirm the role of hepatocyte PPARa in response to fasting and second, to demonstrate the systemic involvement of PPARa in regulating ceramide metabolism during obesity induced by an HFD ("High Fat Diet"). Last, we used p110a liver-specific knockout mice, the catalytic subunit of PI3Kinase alpha. With this model, we confirmed the critical role of p110a-dependent insulin signaling in insulin resistance dissociated from hepatic steatosis induced by a HFD. Interestingly, we demonstrated with this model that free fatty acid released from adipocyte lipolysis (rather than inhibition by p110a-dependent insulin signaling) determines PPARa activity in the liver. Finally, this work highlights the key role of ceramides in lipotoxicity associated with hepatic steatosis.La prévalence de l'obésité et du diabète de type II est en constante augmentation dans les pays industrialisés. La manifestation hépatique de ces pathologies est la NAFLD (" Non-Alcoholic Fatty Liver Disease "). Celle-ci représente aujourd'hui un réel problème de santé publique et résulte d'atteintes métaboliques et hépatiques. La NAFLD démarre par l'accumulation excessive de lipides dans les hépatocytes nommée " stéatose hépatique ". Ces lipides s'accumulent sous différentes formes comme les triglycérides, les esters de cholestérol, les diglycérides et les céramides. La lipotoxicité induite par l'accumulation de ces espèces lipidiques est à l'origine d'un dysfonctionnement au niveau cellulaire et d'une insulino-résistance. Dans ce contexte, les objectifs de ce travail de thèse ont été d'étudier in vivo le rôle des céramides dans l'apparition et les complications de la NAFLD. Pour cela, nous avons utilisé différentes approches : pharmacologiques, génétiques et nutritionnelles. Par une approche pharmacologique, nous avons montré que la fumonisine B1, un contaminant alimentaire ciblant la synthèse des céramides, est à l'origine d'une toxicité hépatique dépendante d'un facteur de transcription essentiel du métabolisme lipidique, LXR (" Liver X Receptor "). Puis, nous avons combiné différentes approches nutritionnelles et génétiques permettant d'induire ou de protéger de la stéatose hépatique. Pour cela, nous avons utilisé des souris invalidées de façon totale ou hépatocyte-spécifique pour PPARa (" Peroxisome Proliferator-Activated Receptor alpha "), un facteur de transcription essentiel au catabolisme des lipides. Cela nous a permis de confirmer le rôle essentiel de PPARa hépatocytaire dans la réponse au jeûne et l'implication systémique de PPARa dans la régulation du métabolisme des céramides au cours de l'obésité induite par un régime HFD (" High Fat Diet "). Enfin, nous avons utilisé des souris invalidées au niveau hépatocytaire pour la sous-unité catalytique de la PI3 Kinase alpha, p110a. Cela nous a permis de confirmer le rôle majeur de la voie de signalisation à l'insuline dépendante de p110a dans l'apparition de l'insulino-résistance dissociée de la stéatose hépatique induite par un régime HFD. De façon intéressante, grâce à ce modèle, nous avons démontré que la lipolyse adipocytaire (et non l'inhibition de la voie insulinémique) représente le signal dominant de l'activité hépatique de PPARa durant le jeûne. L'ensemble de ces travaux mettent en avant le rôle des céramides dans la lipotoxicité associée à la stéatose hépatique

Displacement of an object placed in an electric field: application to micro-assembly

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Influence of surface topography in electrostatic forces simulations for microassembly

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New targets for NAFLD

International audienceNon-alcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease worldwide. It is characterised by steatosis, liver inflammation, hepatocellular injury and progressive fibrosis. Several preclinical models (dietary and genetic animal models) of NAFLD have deepened our understanding of its aetiology and pathophysiology. Despite the progress made, there are currently no effective treatments for NAFLD. In this review, we will provide an update on the known molecular pathways involved in the pathophysiology of NAFLD and on ongoing studies of new therapeutic targets

Electrostatic forces in micromanipulations: review of analytical models and simulations including roughness

Manipulations by contact of objects between 1 μm and 1 mm are often disturbed by adhesion between the manipulated object and the gripper. Electrostatic forces are among the phenomena responsible for this adhesive effect. Analytical models have been developed in the literature to predict the electrostatic forces. Most models are developed within the framework of scanning probe microscopy, i.e. for a contact between a conducting tip and a metallic surface. Models are reviewed in this work and compared with our own simulations using finite elements modeling. The results show a good correlation. The main advantage of our simulations lies in the fact that they can integrate roughness parameters. For this purpose, a fractal representation of the surface topography was chosen through the use of the Weierstrass-Mandelbrot function. Comparisons with experimental benchmarks from the literature show very good correlation between experimental results and simulations. It demonstrates the importance of surface topography on electrostatic forces at very close separation distances. © 2007 Elsevier B.V. All rights reserved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Electrostatic forces and micromanipulator design: on the importance of surface topography parameters

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Gut microbiome, endocrine control of gut barrier function and metabolic diseases

International audienceOverweight and obesity are associated with several cardiometabolic risk factors, including insulin resistance, type 2 diabetes, low-grade inflammation and liver diseases. The gut microbiota is a potential contributing factor regulating energy balance. However, although the scientific community acknowledges that the gut microbiota composition and its activity (e.g. production of metabolites and immune-related compounds) are different between healthy subjects and subjects with overweight/obesity, the causality remains insufficiently demonstrated. The development of low-grade inflammation and related metabolic disorders has been connected with metabolic endotoxaemia and increased gut permeability. However, the mechanisms acting on the regulation of the gut barrier and eventually cardiometabolic disorders are not fully elucidated. In this review, we debate several characteristics of the gut microbiota, gut barrier function and metabolic outcomes. We examine the role of specific dietary compounds or nutrients (e.g. prebiotics, probiotics, polyphenols, sweeteners, and a fructose-rich diet) as well as different metabolites produced by the microbiota in host metabolism, and we discuss how they control several endocrine functions and eventually have either beneficial or deleterious effects on host health