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

Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study

AIMS/HYPOTHESIS: This is an update of the results from the previous report of the CORONADO (Coronavirus SARS-CoV-2 and Diabetes Outcomes) study, which aims to describe the outcomes and prognostic factors in patients with diabetes hospitalised for coronavirus disease-2019 (COVID-19). METHODS: The CORONADO initiative is a French nationwide multicentre study of patients with diabetes hospitalised for COVID-19 with a 28-day follow-up. The patients were screened after hospital admission from 10 March to 10 April 2020. We mainly focused on hospital discharge and death within 28 days. RESULTS: We included 2796 participants: 63.7% men, mean age 69.7 ± 13.2 years, median BMI (25th-75th percentile) 28.4 (25.0-32.4) kg/m(2). Microvascular and macrovascular diabetic complications were found in 44.2% and 38.6% of participants, respectively. Within 28 days, 1404 (50.2%; 95% CI 48.3%, 52.1%) were discharged from hospital with a median duration of hospital stay of 9 (5-14) days, while 577 participants died (20.6%; 95% CI 19.2%, 22.2%). In multivariable models, younger age, routine metformin therapy and longer symptom duration on admission were positively associated with discharge. History of microvascular complications, anticoagulant routine therapy, dyspnoea on admission, and higher aspartate aminotransferase, white cell count and C-reactive protein levels were associated with a reduced chance of discharge. Factors associated with death within 28 days mirrored those associated with discharge, and also included routine treatment by insulin and statin as deleterious factors. CONCLUSIONS/INTERPRETATION: In patients with diabetes hospitalised for COVID-19, we established prognostic factors for hospital discharge and death that could help clinicians in this pandemic period. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04324736

Influence du sexe dans la susceptibilité aux hépatopathies métaboliques

Les hépatopathies non alcooliques (NAFLD) sont aujourd'hui la première cause de maladies hépatiques, et constituent désormais un véritable enjeu de santé publique. Elles sont composées de différents stades d'atteintes, allant de la simple stéatose à la stéato-hépatite (NASH) définie par la présence d'une inflammation hépatique accompagnée ou non de fibrose. Chez l'humain, il existe un fort dimorphisme sexuel dans cette maladie, les femmes sont protégées de cette atteinte, et cette protection disparaît après la ménopause. Les mécanismes liés à cette protection, médiée en partie par les œstrogènes, sont mal connus et il est nécessaire de disposer de modèles précliniques pertinents pour pouvoir les élucider. Nous avons d'abord cherché à identifier un modèle préclinique permettant d'étudier le dimorphisme sexuel dans le contexte de NAFLD. Pour cela, différents régimes hypercaloriques ont été testé (High Fat diet, High Fat diet déficient en choline, Western diet (WD) avec ou sans ajout de glucose et fructose dans l'eau de boisson) sur des souris mâles et femelles C57BL/6J pendant 15 semaines. Des analyses histologiques, biochimiques, transcriptomiques et métabolomiques ont été réalisées. Le régime WD a permis d'obtenir un fort dimorphisme dans la survenue de la NASH. Les mâles ont développé une stéatose sévère associée à une inflammation et un début de fibrose alors que les femelles ont uniquement développé une faible stéatose. Les analyses transcriptomiques ont mis en évidence des réponses géniques très contrastées selon le sexe. L'analyse des réseaux de gènes suggère que les récepteurs nucléaires ont une influence sur le dimorphisme sexuel observé dans notre étude. Parmi les récepteurs nucléaires, ERalpha est le récepteur principalement impliqué dans les effets des œstrogènes dans le foie. Des souris mâles et femelles porteuses de la délétion hépatocytaire d'ERalpha ont reçu le régime WD. L'absence d'ERalpha hépatocytaire n'a pas provoqué de modifications majeures du phénotype hépatique observé en réponse au régime WD dans les deux sexes, suggérant que les œstrogènes sont capables d'agir par l'intermédiaire d'une voie différente. Un autre récepteur nucléaire, PPARalpha, joue un rôle majeur dans le métabolisme des lipides et est protecteur vis-à-vis de la stéatose. Chez le mâle, il est montré que l'absence de PPARalpha provoque un défaut du catabolisme des lipides durant le jeûne. Afin d'étudier l'éventuelle activité dimorphique de PPARalpha, l'effet d'un jeûne prolongé chez les femelles a été analysé. Les résultats obtenus in vivo montrent qu'en l'absence de PPARalpha hépatocytaire, l'induction de la cétogenèse est altérée, quel que soit le sexe. Cependant, l'analyse du profil d'expression génique hépatique révèle une activité sexuellement dimorphique de PPARalpha. PPARalpha hépatocytaire a ensuite été étudié dans un contexte de NAFLD induit par un régime WD. De manière assez inattendue, l'absence de PPARalpha dans les hépatocytes n'a pas provoqué d'aggravation de la NAFLD induite par le régime quel que soit le sexe. En revanche, la délétion de PPARalpha a provoqué une absence de prise de poids sous régime WD, uniquement chez les mâles. L'ensemble des résultats de cette thèse montre un important dimorphisme sexuel vis-à-vis de la NAFLD induite par un régime hypercalorique, associé à des réponses transcriptomiques et métabolomiques différentes entre les mâles et les femelles. Les récepteurs nucléaires ERalpha et PPARalpha, bien qu'ayant une activité transcriptionnelle dimorphique, ne sont pas des facteurs déterminants de la protection des femelles dans la NAFLD.Non Alcoholic Fatty Liver Disease (NAFLD), ranging from steatosis to steatohepatitis (NASH), is the most common liver disease and a major public health issue worldwide. There are strong clinical and preclinical evidence for sexual dimorphism. The establishment of reliable animal models is essential to understand the mechanisms underlying such gender specific susceptibility to the disease. We aimed at identifying a mouse model of NAFLD that replicates at best the sexual dimorphism observed in humans. We tested different hypercaloric diets: High-Fat Diet (HFD), Choline Deficient HFD, Western Diet enriched with cholesterol and co-administered or not with drinking water containing glucose and fructose in male and female C57BL/6J mice (n=12/group). Histological, biochemical, transcriptomic and metabolomic analyses were performed. The Western Diet induces a strong dimorphic phenotype for the onset of NASH. Males develop major steatosis associated with severe inflammation and fibrosis whereas females show much less steatosis. Both sexes develop obesity and have impaired glucose tolerance. In contrast, insulin resistance is more severe in males than in females. Finally, liver transcriptome analysis highlights contrasted gene expression profiles between males and females in response to the different diets. Gene network analysis suggest that nuclear receptors are influential in this sexual dimorphic response to dietary challenges. Among nuclear receptors, ERalpha is the major effector of estrogen signaling in the liver. We tested the western diet in male and female mice in absence of ERalpha in hepatocytes. This deletion did not cause significant changes in hepatic phenotype in response to western diet in males and females. Another nuclear receptor has been studied, PPARalpha plays a central role in lipid metabolism and is protective against NAFLD. In the absence of PPARalpha in hepatocytes, fatty acid catabolism is defective during fasting in male mice. Therefore, to investigate whether hepatocyte PPARalpha activity shows sexual dimorphism, we tested the effect of fasting in female mice. In vivo experiments in mice with a hepatocyte specific knock-out of PPARalpha reveal that fasting induces similar PPARalpha-dependent ketogenesis in mice from both sexes. However, gene expression profiling reveals sexual dimorphic activity of hepatocyte PPARalpha. In females, the absence of PPARalpha specifically upregulates an extensive set of genes involved in inflammatory response. Next, we tested the western diet in these mice and unexpectedly, the absence of hepatocyte PPARalpha did not exacerbate the NAFLD in both sexes. Altogether, this preclinical work shows an important sexual dimorphism in diet-induced NAFLD with a significant different transcriptomic and metabolomic response between male and female mice. PPARalpha, a key transcription factor in the liver homeostasis, shows sexual dimorphic activity but does not seem to contribute to female protection against metabolic liver diseases

Sexual dimorphic susceptibility to NAFLD

Les hépatopathies non alcooliques (NAFLD) sont aujourd'hui la première cause de maladies hépatiques, et constituent désormais un véritable enjeu de santé publique. Elles sont composées de différents stades d'atteintes, allant de la simple stéatose à la stéato-hépatite (NASH) définie par la présence d'une inflammation hépatique accompagnée ou non de fibrose. Chez l'humain, il existe un fort dimorphisme sexuel dans cette maladie, les femmes sont protégées de cette atteinte, et cette protection disparaît après la ménopause. Les mécanismes liés à cette protection, médiée en partie par les œstrogènes, sont mal connus et il est nécessaire de disposer de modèles précliniques pertinents pour pouvoir les élucider. Nous avons d'abord cherché à identifier un modèle préclinique permettant d'étudier le dimorphisme sexuel dans le contexte de NAFLD. Pour cela, différents régimes hypercaloriques ont été testé (High Fat diet, High Fat diet déficient en choline, Western diet (WD) avec ou sans ajout de glucose et fructose dans l'eau de boisson) sur des souris mâles et femelles C57BL/6J pendant 15 semaines. Des analyses histologiques, biochimiques, transcriptomiques et métabolomiques ont été réalisées. Le régime WD a permis d'obtenir un fort dimorphisme dans la survenue de la NASH. Les mâles ont développé une stéatose sévère associée à une inflammation et un début de fibrose alors que les femelles ont uniquement développé une faible stéatose. Les analyses transcriptomiques ont mis en évidence des réponses géniques très contrastées selon le sexe. L'analyse des réseaux de gènes suggère que les récepteurs nucléaires ont une influence sur le dimorphisme sexuel observé dans notre étude. Parmi les récepteurs nucléaires, ERalpha est le récepteur principalement impliqué dans les effets des œstrogènes dans le foie. Des souris mâles et femelles porteuses de la délétion hépatocytaire d'ERalpha ont reçu le régime WD. L'absence d'ERalpha hépatocytaire n'a pas provoqué de modifications majeures du phénotype hépatique observé en réponse au régime WD dans les deux sexes, suggérant que les œstrogènes sont capables d'agir par l'intermédiaire d'une voie différente. Un autre récepteur nucléaire, PPARalpha, joue un rôle majeur dans le métabolisme des lipides et est protecteur vis-à-vis de la stéatose. Chez le mâle, il est montré que l'absence de PPARalpha provoque un défaut du catabolisme des lipides durant le jeûne. [...]Non Alcoholic Fatty Liver Disease (NAFLD), ranging from steatosis to steatohepatitis (NASH), is the most common liver disease and a major public health issue worldwide. There are strong clinical and preclinical evidence for sexual dimorphism. The establishment of reliable animal models is essential to understand the mechanisms underlying such gender specific susceptibility to the disease. We aimed at identifying a mouse model of NAFLD that replicates at best the sexual dimorphism observed in humans. We tested different hypercaloric diets: High-Fat Diet (HFD), Choline Deficient HFD, Western Diet enriched with cholesterol and co-administered or not with drinking water containing glucose and fructose in male and female C57BL/6J mice (n=12/group). Histological, biochemical, transcriptomic and metabolomic analyses were performed. The Western Diet induces a strong dimorphic phenotype for the onset of NASH. Males develop major steatosis associated with severe inflammation and fibrosis whereas females show much less steatosis. Both sexes develop obesity and have impaired glucose tolerance. In contrast, insulin resistance is more severe in males than in females. Finally, liver transcriptome analysis highlights contrasted gene expression profiles between males and females in response to the different diets. Gene network analysis suggest that nuclear receptors are influential in this sexual dimorphic response to dietary challenges. Among nuclear receptors, ERalpha is the major effector of estrogen signaling in the liver. We tested the western diet in male and female mice in absence of ERalpha in hepatocytes. This deletion did not cause significant changes in hepatic phenotype in response to western diet in males and females. Another nuclear receptor has been studied, PPARalpha plays a central role in lipid metabolism and is protective against NAFLD. In the absence of PPARalpha in hepatocytes, fatty acid catabolism is defective during fasting in male mice. Therefore, to investigate whether hepatocyte PPARalpha activity shows sexual dimorphism, we tested the effect of fasting in female mice. In vivo experiments in mice with a hepatocyte specific knock-out of PPARalpha reveal that fasting induces similar PPARalpha-dependent ketogenesis in mice from both sexes.[...

Expert opinion on immunotherapy induced diabetes

IF 1.444 (2017)International audienceImmunotherapy often incurs side-effects, mainly involving the skin, digestive tract and endocrine system. The most frequent endocrine side-effects involve the pituitary and thyroid glands. Cases of insulin-dependent diabetes, whether autoimmune or not (type 1 or 1B) have been reported with PD-1/PD-L1 inhibitors, alone or in association with anti-CTLA-4 antibodies, and were systematically associated with sudden-onset insulinopenia, frequently leading to ketoacidosis or fulminant diabetes, requiring first-line insulin therapy. This adverse effect has not so far been reported with anti-CTLA-4 monotherapy

Expert opinion on the metabolic complications of mTOR inhibitors

IF 1.444 (2017)International audienceUsing mTOR inhibitors (mTORi) as anticancer drugs led to hyperglycemia (12-50%) and hyperlipidemia (7-73%) in phase-III trials. These high rates require adapted treatment in cancer patients. Before initiating mTORi treatment, lipid profile screening should be systematic, with fasting glucose assay in non-diabetic patients and HbA1C in diabetic patients. After initiation, lipid profile monitoring should be systematic, with fasting glucose assay in non-diabetic patients, every 2 weeks for the first month and then monthly. The HbA1C target is≤8%, before and after treatment initiation in known diabetic patients and in case of onset of diabetes under mTORi. LDL-cholesterol targets should be adapted to general health status and cardiovascular and oncologic prognosis. If treatment is indicated, pravastatin should be prescribed in first line; atorvastatin and simvastatin are contraindicated. Fenofibrate should be prescribed for hypertriglyceridemia>5g/l resisting dietary measures adapted to oncologic status. In non-controllable hypertriglyceridemia exceeding 10g/l, mTORi treatment should be interrupted and specialist opinion should be sought.L’utilisation des inhibiteurs mTOR (mTORi) comme anticancéreux est responsable d’hyperglycémies (12–50 %) et d’hyperlipidémies (7–73 %) dans les études de phase III. Ces chiffres élevés justifient une prise en charge adaptée à la population oncologique. Avant l’instauration d’un traitement par mTORi, nous recommandons la réalisation d’une exploration d’une anomalie lipidique (EAL) chez tous les patients, d’une glycémie à jeun chez les patients non diabétiques et d’une HbA1C chez les patients diabétiques. Après instauration du traitement, une surveillance de l’EAL (tous patients) et de la glycémie à jeun (patients non diabétique) est recommandée tous les 15 jours le premier mois puis mensuellement. Nous recommandons un objectif d’HbA1C inférieur ou égal à 8 %, avant et après l’instauration du traitement chez les patients diabétiques connus et en cas d’apparition d’un diabète sous mTORi. Les objectifs de LDL-cholestérol devront être adaptés à l’état général et aux pronostics cardiovasculaire et oncologique du patient. En cas d’introduction d’un traitement, la pravastatine sera prescrite en première intention ; l’atorvastatine et la simvastatine sont contre-indiquées. Nous recommandons l’instauration de fénofibrate en cas d’hypertriglycéridémie > 5 g/L résistante aux mesures diététiques adaptées à l’état oncologique du patient. En cas d’hypertriglycéridémie non contrôlable > 10 g/L, nous suggérons la suspension temporaire de mTORi et la prise d’un avis spécialisé

Genetic Inhibition of PCSK9 and Liver Function

International audienceInhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab) or with small-interfering RNAs (inclisiran) lowers plasma low-density lipoprotein cholesterol (LDL-C) levels, a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). 1,2 So far, the pharmacologic inhibition of PCSK9 presents with a favorable safety profile, but longer-term safety remains to be proven. Studies in preclinical models and in humans have suggested a potential link between PCSK9 deficiency and the risk of nonalcoholic fatty liver disease (NAFLD), 3,4 a spectrum of progressive liver diseases ranging from simple steatosis to fibrosis that can lead to cirrhosis and hepatocellular carcinoma. Notably, it has been shown that PCSK9 knockout mice are more prone to develop severe hepatic steatosis and fibrosis when receiving a high-fat diet. 3 This study aims to study the associations of the lifelong genetic inhibition of PCSK9 with plasma liver enzymes and NAFLD by using the loss-of-function variant PCSK9p.Arg46Leu as a genetic instrument. For comparison, we used 2 variants in PNPLA3 and TM6SF2, known to be involved in the pathogenesis of NAFLD. 5 Methods | Approval. Both the UK Biobank and the Electronic Medical Record and Genomics (eMERGE) cohort have obtained regulatory approvals, and all participants provided written informed consent. Because the data were publicly available, we did not obtain specific approval for this study. UK-Biobank Data Sets. Genetic associations with biologic traits (plasma circulating liver enzymes) in the UK-Biobank cohort were extracted from the second-round results (released August 1, 2018) by the Nealelab (see description in http://www. nealelab.is/uk-biobank/). These data were obtained from 361 194 participants (194 174 women and 167 020 men) of the UK-Biobank cohort (https://www.ukbiobank.ac.uk)

Avis d’experts sur les complications metaboliques des nouvelles therapies anti-cancereuses: inhibiteurs tyrosine kinase

International audienceTyrosine kinase inhibitors (TKI) interfere with glucose metabolism. Contrasting effects have been reported, even for a given molecule. Hyperglycemia rates range between 15 and 40%; nilotinib seems to be the molecule most liable to induce diabetes. Metabolic effects range from metabolic syndrome to onset of diabetes, requiring treatment based on insulin resistance, although pathophysiology is unclear. It is noteworthy that fulminant diabetes has never been reported under TKIs. TKIs may lead to hypoglycemia in type 1 or 2 diabetes. Several cases have been reported of improvement in glycemia and in HbA1c, with reduction or even termination of insulin therapy, mainly under imatinib and sunitinib. Fasting glucose levels should be checked before, during and after treatment, plus HbA1C in diabetic patients, with reinforced self-monitoring. These side-effects are transient and never contraindicate continuation of TKIs. Dyslipidemia under TKI has been reported, concerning both LDL-cholesterol and triglycerides. Although variations seem to be slight, lipid assessment is recommended before, during and after treatment.Les inhibiteurs des tyrosines kinases (ITK) interfèrent avec le métabolisme glucidique., Des effets opposés ont été décrits avec ces thérapies, parfois avec une même molécule. La fréquence des hyperglycémies varient de 15 à 40%, le nilotinib apparait être la molécule la plus diabétogène. Ces modifications métaboliques vont du syndrome métabolique à l’apparition d’un diabète, pouvant justifier la mise en place de traitement jouant sur l’insulino-résistance, bien que les explications physiopathologiques restent peu claires. A noter qu’aucun diabète fulminant n’a été décrit sous ITK. Les ITK peuvent exercer un effet hypoglycémiant chez des patients diabétiques de type 1 et 2. Plusieurs cas ont été rapportés avec amélioration des glycémies et de l’HbA1c, réduction voire arrêt de l’insulinothérapie, essentiellement avec l’imatinib et le sunitinib. La glycémie à jeun devra être contrôlée avant, pendant le traitement et après son arrêt, ainsi que l’HbA1C chez les patients diabétiques, avec une auto-surveillance glycémique renforcée. Ces effets secondaires sont transitoires et ne contre-indiquent, en aucun cas, la poursuite de l’ITK.>Des dyslipidémies ont été décrites sous ITK, portant à la fois sur le LDL-cholestérol et les triglycérides. Bien que ces variations semblent minimes, il est recommandé de contrôler un bilan lipidique avant, pendant le traitement et après son arrêt

Sex differences in metabolic regulation and diabetes susceptibility

International audienceGender and biological sex impact the pathogenesis of numerous diseases, including metabolic disorders such as diabetes. In most parts of the world, diabetes is more prevalent in men than in women, especially in middle-aged populations. In line with this, considering almost all animal models, males are more likely to develop obesity, insulin resistance and hyperglycaemia than females in response to nutritional challenges. As summarised in this review, it is now obvious that many aspects of energy balance and glucose metabolism are regulated differently in males and females and influence their predisposition to type 2 diabetes. During their reproductive life, women exhibit specificities in energy partitioning as compared with men, with carbohydrate and lipid utilisation as fuel sources that favour energy storage in subcutaneous adipose tissues and preserve them from visceral and ectopic fat accumulation. Insulin sensitivity is higher in women, who are also characterised by higher capacities for insulin secretion and incretin responses than men; although, these sex advantages all disappear when glucose tolerance deteriorates towards diabetes. Clinical and experimental observations evidence the protective actions of endogenous oestrogens, mainly through oestrogen receptor α activation in various tissues, including the brain, the liver, skeletal muscle, adipose tissue and pancreatic beta cells. However, beside sex steroids, underlying mechanisms need to be further investigated, especially the role of sex chromosomes, fetal/neonatal programming and epigenetic modifications. On the path to precision medicine, further deciphering sex-specific traits in energy balance and glucose homeostasis is indeed a priority topic to optimise individual approaches in type 2 diabetes prevention and treatment