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The intestine, like the liver and kidney, in various vertebrates and humans is able to carry out gluconeogenesis and release glucose into the blood. In the fed post-absorptive state, intestinal glucose is sensed by the gastrointestinal nervous system. The latter initiates a signal to the brain regions controlling energy homeostasis and stress-related behaviour. Intestinal gluconeogenesis (IGN) is activated by several complementary mechanisms, in particular nutritional situations (for example, when food is enriched in protein or fermentable fibre and after gastric bypass surgery in obesity). In these situations, IGN has several metabolic and behavioural benefits. As IGN is activated by nutrients capable of fuelling systemic gluconeogenesis, IGN could be a signal to the brain that food previously ingested is suitable for maintaining plasma glucose for a while. This process might account for the benefits observed. Finally, in this Perspective, we discuss how the benefits of IGN in fasting and fed states could explain why IGN emerged and was maintained in vertebrates by natural selection.

Intestinal gluconeogenesis (IGN), gastric bypass (GBP) and gut microbiota positively regulate glucose homeostasis and diet-induced dysmetabolism. GBP modulates gut microbiota, whether IGN could shape it has not been investigated. We studied gut microbiota and microbiome in wild type and IGN-deficient mice, undergoing GBP or not, and fed on either a normal chow (NC) or a high-fat/high-sucrose (HFHS) diet. We also studied fecal and urine metabolome in NC-fed mice. IGN and GBP had a different effect on the gut microbiota of mice fed with NC and HFHS diet. IGN inactivation increased abundance of Deltaproteobacteria on NC and of Proteobacteria such as Helicobacter on HFHS diet. GBP increased abundance of Firmicutes and Proteobacteria on NC-fed WT mice and of Firmicutes, Bacteroidetes and Proteobacteria on HFHS-fed WT mice. The combined effect of IGN inactivation and GBP increased abundance of Actinobacteria on NC and the abundance of Enterococcaceae and Enterobacteriaceae on HFHS diet. A reduction was observed in the amounf of short-chain fatty acids in fecal (by GBP) and in both fecal and urine (by IGN inactivation) metabolome. IGN and GBP, separately or combined, shape gut microbiota and microbiome on NC- and HFHS-fed mice, and modify fecal and urine metabolome.

Thyroid hormone (T3) and its nuclear receptors (TR) are important regulators of energy expenditure and adaptive thermogenesis, notably through their action in the brown adipose tissue (BAT). However, T3 acts in many other peripheral and central tissues which are also involved in energy expenditure. The general picture of how T3 regulates BAT thermogenesis is currently not fully established, notably due to the absence of extensive omics analyses and the lack of specific mice model. Here, we first used transcriptome and cistrome analyses to establish the list of T3/TR direct target genes in brown adipocytes. We then developed a novel model of transgenic mice, in which T3-signaling is specifically suppressed in brown adipocytes at adult stage. We addressed the capacity of these mice to mount a thermogenic response when challenged by either a cold exposure or a high-fat diet, and analyzed the associated changes in BAT transcriptome. We conclude that T3 plays a crucial role in the thermogenic response of the BAT, controlling the expression of genes involved in lipid and glucose metabolism and regulating BAT proliferation. The resulting picture provides an unprecedented view on the pathways by which T3 activates energy expenditure through an efficient adaptive thermogenesis in the BAT.Significance StatementThyroid hormones (TH) increase energy expenditure by regulating the expression of target genes in many metabolic tissues. Among them, brown adipose tissue (BAT) dissipates biochemical energy into heat production to notably prevent hypothermia during cold exposure. Hypothyroid mice display inefficient BAT thermogenesis suggesting that TH are crucial for this process. Here, we eliminated TH signaling specifically in brown adipocytes and expose the mice to different physiological stressors. We showed that TH signaling is crucial for BAT thermogenesis as it controls the expression of genes involved in proliferation and in the metabolism of lipids and glucose, the main energy resources for BAT thermogenesis. This study provides an unprecedented view on the pathways by which T3 activates energy expenditure the BAT.

Introduction: Several studies have suggested that diet, especially the one enriched in microbiota-fermented fibers or fat, regulates behavior. The underlying mechanisms are currently unknown. We previously reported that certain macronutrients (fermentable fiber and protein) regulate energy homeostasis via the activation of intestinal gluconeogenesis (IGN), which generates a neural signal to the brain. We hypothesized that these nutriments might control behavior using the same gut-brain circuit. Methods: Wild-type and IGN-deficient mice were fed chow or diets enriched in protein or fiber. Changes in their behavior were assessed using suited tests. Hippocampal neurogenesis, extracellular levels of serotonin, and protein expression levels were assessed by immunofluorescence, in vivo dialysis, and Western blotting, respectively. IGN was rescued by infusing glucose into the portal vein of IGN-deficient mice. Results: We show here that both fiber- and protein-enriched diets exert beneficial actions on anxiety-like and depressive-like behaviors. These benefits do not occur in mice lacking IGN. Consistently, IGN-deficient mice display hallmarks of depressive-like disorders, including decreased hippocampal neurogenesis, basal hyperactivity, and deregulation of the hypothalamic-pituitary-adrenal axis, which are associated with increased expression of the precursor of corticotropin-releasing hormone in the hypothalamus and decreased expression of the glucocorticoid receptor in the hippocampus. These neurobiological alterations are corrected by portal glucose infusion mimicking IGN. Conclusion: IGN translates nutritional information, allowing the brain to finely coordinate energy metabolism and behavior.

Citation suggérée : Anses. (2021). Avis relatif à l’évaluation des risques liés aux niveaux d’activité physique et de sédentarité de la population des adultes de 18 à 65 ans, hors femmes enceintes et ménopausées. (saisine 2017-SA-0064_b). Maisons-Alfort : Anses, 109 p.; L’Agence française de sécurité sanitaire de l’alimentation, de l’environnement et du travail (Anses) s’est autosaisie le 29 mars 2017 afin d’évaluer les risques liés aux niveaux d’activité physique et de sédentarité des adultes de 18 à 64 ans, hors femmes enceintes et ménopausées, à partir des données recueillies en 2014-2015 de l’étude individuelle et nationale sur les consommations alimentaires Inca3.Cette autosaisine s’inscrit dans la continuité du rapport de l’Anses publié en février 2016, intitulé « Actualisation des repères du PNNS - Révisions des repères relatifs à l’activité physique et à la sédentarité » (Anses 2016).Le PNNS (Programme national de nutrition santé) est un programme national de santé publique qui vise à améliorer l’état de santé de la population en agissant sur la nutrition, déterminant majeur de l’état de santé. S’agissant de l’importance de l’activité physique, le PNNS mentionne notamment « les repères nutritionnels du PNNS visant à promouvoir une alimentation et une activité physique favorables à un état nutritionnel et un état de santé optimaux. » Depuis la publication du rapport de l’Anses (2016), de nombreuses études de cohorte ont été publiées, apportant de nouveaux éclairages sur l'effet de différents comportements d’activité physique et de sédentarité sur la santé. L'évaluation des niveaux d'activité physique (NAP) et de temps de sédentarité a permis d'obtenir des données plus objectives permettant d'étudier la répartition de différents comportements dans la journée et les liens de ces comportements entre eux et avec des facteurs de santé.Cette autosaisine repose sur le fonds scientifique suivant :- le rapport « Actualisation des repères du PNNS - Révisions des repères relatifs à l’activité physique et à la sédentarité » (Anses 2016) ;- les données issues de l’Etude individuelle et nationale sur les consommations alimentaires Inca 3 (Anses 2017) ;- les données sur les risques associés aux niveaux d'activité physique et de sédentarité issues de la littérature ; celles-ci portent sur l’activité physique de loisir c’est-à-dire hors du contexte professionnel.

ObjectiveIntestinal gluconeogenesis, via the initiation of a gut-brain nervous circuit, accounts for the metabolic benefits linked to dietary proteins or fermentable fibre in rodents and has been positively correlated with the rapid amelioration of body weight after gastric bypass surgery in obese humans. In particular, the activation of intestinal gluconeogenesis moderates the development of hepatic steatosis accompanying obesity. In this study, we investigated the specific effects of intestinal gluconeogenesis on adipose tissue metabolism, independently of its induction by nutritional manipulation.MethodsWe used two transgenic mouse models of suppression or overexpression of G6PC, the catalytic subunit of glucose-6 phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine.ResultsUnder a hypercaloric diet, mice with a genetic overexpression of intestinal gluconeogenesis showed a lower adiposity and higher thermogenic capacities than wild-type mice, featuring marked browning of white adipose tissue and prevention of the whitening of brown adipose tissue. Suppression of sympathetic nervous signalling in brown adipose tissue impairs the activation of thermogenesis. Conversely, mice with genetic suppression of intestinal gluconeogenesis exhibit an increase in adiposity under standard diet, associated with a decreased expression of markers of thermogenesis in both the brown and white adipose tissues.ConclusionIntestinal gluconeogenesis is sufficient in itself to activate the sympathetic nervous system and prevent the expansion and the metabolic alterations of brown and white adipose tissues metabolism under high calorie diet, thus preventing the development of obesity. These data increase knowledge of the mechanisms of weight reduction in gastric bypass surgery and pave the way of new approaches to prevent or cure obesity.

Objectif La neoglucogenese intestinale (NGI) est une fonction benefique dans l’homeostasie energetique. Chez la souris, son induction par les fibres diminue le poids et la masse grasse, alors que son absence favorise la prise de poids, suggerant ainsi qu’elle pourrait moduler le metabolisme du tissu adipeux. Nous proposons que la NGI pourrait ameliorer le bilan energetique en modulant la thermogenese du tissu adipeux brun (TAB), en impliquant son principal regulateur: le systeme nerveux sympathique (SNS). Methodes Nous avons etudie la thermogenese du TAB et l’implication du SNS, de souris qui surexpriment dans l’intestin (I.G6pcsurexp) la glucose-6-phosphatase, l’enzyme cle de la production endogene de glucose, nourries avec un regime standard et hypercalorique. Resultats Les souris I.G6pcsurexp sous regime hypercalorique sont protegees de l’obesite, et presentent une temperature rectale et un degagement de chaleur par le TAB augmentes. De plus, ces souris ont une plus faible adiposite, associee a un plus fort niveau d’expression des marqueurs de la thermogenese. L’augmentation de l’expression de la tyrosine hydroxylase dans le TAB suggere que la NGI pourrait exercer ses effets via le SNS. Par ailleurs, alors que les souris I.G6pcsurexp (regime standard) maintiennent mieux leur temperature corporelle lors d’une exposition au froid (6 °C–4 h), cette amelioration est absente apres inactivation chimique du SNS innervant le TAB. Discussion L’activation de la NGI est capable de prevenir le developpement de l’obesite et le blanchiment du TAB associe, en activant la thermogenese via un axe nerveux intestin-cerveau-TAB impliquant le SNS.

Tamoxifen is a selective estrogen receptor modulator used to activate the CREERT2 recombinase, allowing tissue-specific and temporal control of the somatic mutagenesis to generate transgenic mice. Studies integrating development and metabolism require a genetic modification induced by a neonatal tamoxifen administration. Here, we investigate the effects of a neonatal tamoxifen administration on energy homeostasis in adult male and female C57BL/6J mice. C57BL/6J male and female mouse pups received a single injection of tamoxifen 1 day after birth (NTT) and were fed a high-fat/high-sucrose diet at 6 weeks of age. We measured weight, body composition, glucose and insulin tolerance, basal metabolism, and tibia length and weight in adult mice. The neonatal tamoxifen administration exerted long-term, sex-dependent effects on energy homeostasis. NTT female mice became overweight and developed impaired glucose control in comparison to vehicle-treated littermates. NTT females exhibited 60% increased fat mass, increased food intake, decreased physical activity and energy expenditure, impaired glucose and insulin tolerance, and fasting hyperglycemia and hyperinsulinemia. In contrast, NTT male mice exhibited a modest amelioration of glucose and insulin tolerance and long-term decreased lean mass linked to decreased bone weight. These results suggest that the neonatal tamoxifen administration exerted a marked and sex-dependent influence on adult energy homeostasis and bone weight and must therefore be used with caution for the development of transgenic mouse models regarding studies on energy homeostasis and bone biology.

Citation suggérée : Anses. (2021). Actualisation des références nutritionnelles en vitamines et minéraux pour les populations spécifiques (nourrissons, enfants, adolescents, femmes enceintes ou allaitantes et personnes âgées). (saisine 2018-SA-0238). Maisons-Alfort : Anses, 239 p.; En 2016, l’Anses a proposé une mise à jour des références nutritionnelles pour la population adulte (femmes de 18 à 54 ans et hommes de 18 à 64 ans) dans le cadre de l’actualisation des repères de consommation alimentaire (saisine 2012-SA-0103). Par la suite, des rapports dédiés aux repères de consommation alimentaire pour les populations spécifiques (personnes âgées, enfants, femmes enceintes et allaitantes) ont été publiés en 2019, sans toutefois quede nouvelles références nutritionnelles ne soient définies par l’agence.Par ailleurs, la mise à jour de 2016 n’a concerné que les vitamines et minéraux indispensables pour lesquelles des données de consommation étaient disponibles. De ce fait, la vitamine B8, la vitamine K, le chrome, le molybdène, les chlorures et le fluor n’avaient pas été traités.

En 2016, l’Anses a proposé une mise à jour des références nutritionnelles pour la population adulte (femmes de 18 à 54 ans et hommes de 18 à 64 ans) dans le cadre de l’actualisation des repères de consommation alimentaire (saisine 2012-SA-0103). Par la suite, des rapports dédiésaux repères de consommation alimentaire pour les populations spécifiques (personnes âgées, enfants, femmes enceintes et allaitantes) ont été publiés en 2019, sans toutefois que de nouvelles références nutritionnelles ne soient définies par l’agence.Par ailleurs, la mise à jour de 2016 n’a concerné que les vitamines et minéraux indispensables pour lesquelles des données de consommation étaient disponibles. De ce fait, la vitamine B8, la vitamine K, le chrome, le molybdène, les chlorures et le fluor n’avaient pas été traités.

International audience; High-protein meals and foods are promoted for their beneficial effects on satiety, weight loss and glucose homeostasis. However, the mechanisms involved and the long-term benefits of such diets are still debated. We here review how the characterisation of intestinal gluconeogenesis (IGN) sheds new light on the mechanisms by which protein diets exert their beneficial effects on health. The small intestine is the third organ (in addition to the liver and kidney) contributing to endogenous glucose production via gluconeogenesis. The particularity of glucose produced by the intestine is that it is detected in the portal vein and initiates a nervous signal to the hypothalamic nuclei regulating energy homeostasis. In this context, we demonstrated that protein diets initiate their satiety effects indirectly via IGN and portal glucose sensing. This induction results in the activation of brain areas involved in the regulation of food intake. The μ-opioid-antagonistic properties of protein digests, exerted in the portal vein, are a key link between IGN induction and protein-enriched diet in the control of satiety. From our results, IGN can be proposed as a mandatory link between nutrient sensing and the regulation of whole-body homeostasis. The use of specific mouse models targeting IGN should allow us to identify several metabolic functions that could be controlled by protein diets. This will lead to the characterisation of the mechanisms by which protein diets improve whole-body homeostasis. These data could be the basis of novel nutritional strategies targeting the serious metabolic consequences of both obesity and diabetes.

ObjectiveHepatic steatosis accompanying obesity is a major health concern, since it may initiate non-alcoholic fatty liver disease (NAFLD) and associated complications like cirrhosis or cancer. Intestinal gluconeogenesis (IGN) is a recently described function that contributes to the metabolic benefits of specific macronutrients as protein or soluble fibre, via the initiation of a gut-brain nervous signal triggering brain-dependent regulations of peripheral metabolism. Here, we investigate the effects of IGN on liver metabolism, independently of its induction by the aforementioned macronutrients.DesignTo study the specific effects of IGN on hepatic metabolism, we used two transgenic mouse lines: one is knocked down for and the other overexpresses glucose-6-phosphatase, the key enzyme of endogenous glucose production, specifically in the intestine.ResultsWe report that mice with a genetic overexpression of IGN are notably protected from the development of hepatic steatosis and the initiation of NAFLD on a hypercaloric diet. The protection relates to a diminution of de novo lipogenesis and lipid import, associated with benefits at the level of inflammation and fibrosis and linked to autonomous nervous system. Conversely, mice with genetic suppression of IGN spontaneously exhibit increased hepatic triglyceride storage associated with activated lipogenesis pathway, in the context of standard starch-enriched diet. The latter is corrected by portal glucose infusion mimicking IGN.ConclusionWe conclude that IGN per se has the capacity of preventing hepatic steatosis and its eventual evolution toward NAFLD.

Little is known about the jejunal insulin signalling pathways in insulin resistance/diabetes states and their possible regulation by insulin/leptin. We study in jejunum the relation between insulin signalling and insulin resistance in morbidly obese subjects with low (MO-low-IR) or with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2DM)), and the effect of insulin/leptin on intestinal epithelial cells (IEC). Insulin receptor substrate-1 (IRS1) and the catalytic p110&beta, subunit (p110&beta, ) of phosphatidylinositol 3-kinase (PI3K) were higher in MO-high-IR than in MO-low-IR. The regulatory p85&alpha, subunit of PI3K (p85&alpha, )/p110&beta, ratio was lower in MO-high-IR and MO-metf-T2DM than in MO-low-IR. Akt-phosphorylation in Ser473 was reduced in MO-high-IR compared with MO-low-IR. IRS1 and p110-&beta, were associated with insulin and leptin levels. The improvement of body mass index (BMI) and HOMA-IR (homeostasis model assessment of insulin resistance index) after bariatric surgery was associated with a higher IRS1 and a lower p85&alpha, /p110&beta, ratio. IEC (intestinal epithelial cells) incubation with a high glucose + insulin dose produced an increase of p85&alpha, and p110&beta, High dose of leptin produced an increase of IRS1, p85&alpha, In conclusion, despite the existence of insulin resistance, the jejunal expression of genes involved in insulin signalling was increased in MO-high-IR. Their expressions were regulated mainly by leptin. IRS1 and p85&alpha, ratio was associated with the evolution of insulin resistance after bariatric surgery.

Introduction: Intestinal gluconeogenesis (IGN) exerts metabolic benefits in energy homeostasis via the neural sensing of portal glucose. Objective: The aim of this work was to determine central mechanisms involved in the effects of IGN on the control of energy homeostasis. Methods: We investigated the effects of glucose infusion into the portal vein, at a rate that mimics IGN, in conscious wild-type, leptin-deficient Ob/Ob and calcitonin gene-related peptide (CGRP)-deficient mice. Results: We report that portal glucose infusion decreases food intake and plasma glucose and induces in the hypothalamic arcuate nucleus (ARC) the phosphorylation of STAT3, the classic intracellular messenger of leptin signaling. This notably takes place in POMC-expressing neurons. STAT3 phosphorylation does not require leptin, since portal glucose effects are observed in leptin-deficient Ob/Ob mice. We hypothesized that the portal glucose effects could require CGRP, a neuromediator previously suggested to suppress hunger. In line with this hypothesis, neither the metabolic benefits nor the phosphorylation of STAT3 in the ARC take place upon portal glucose infusion in CGRP-deficient mice. Moreover, intracerebroventricular injection of CGRP activates hypothalamic phosphorylation of STAT3 in mice, and CGRP does the same in hypothalamic cells. Finally, no metabolic benefit of dietary fibers (known to depend on the induction of IGN), takes place in CGRP-deficient mice. Conclusions: CGRP-induced phosphorylation of STAT3 in the ARC is part of the neural chain determining the hunger-modulating and glucose-lowering effects of IGN/portal glucose.

International audience; Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.

Introduction/objectif Le glucose issu de la neoglucogenese hepatique est transporte hors des hepatocytes par le transporteur GLUT2. En utilisant un modele d’invalidation totale de la Caveoline 1 (Cav1), nous avons montre que le glucose neoglucogenique etait egalement exporte par une voie vesiculaire dependante de cette proteine. L’objectif de ce projet est de determiner le role de cette voie vesiculaire de production de glucose sur le metabolisme energetique et glucidique. Materiel et methodes Nous avons etudie chez des souris mâles et femelles sauvages et L.Cav1-/− (modele d’invalidation hepato-specifique de la Cav1) : le metabolisme energetique (suivi de poids, prise alimentaire, depense energetique) et glucidique (tests de tolerance au glucose et a l’insuline, clamp hyperinsulinemique-euglycemique) apres trois mois de regime standard ou de regime riche en graisse et en sucre (high fat-high sucrose (HFHS)). Resultats Le foie des souris L.Cav1-/− produit moins de glucose. Les souris L.Cav1-/− sont protegees de la prise de poids (51,7 ± 1,0 vs 46,3 ± 1,2, p = 0,01) et de l’alteration de la tolerance au glucose induites par un regime HFHS. Sous regime standard, les souris L.Cav1-/− presentent egalement une moindre prise de poids (35,6 ± 0,70 vs 33,1 ± 0,72, p = 0,03) et une amelioration de la tolerance au glucose et de la sensibilite a l’insuline. Discussion L’inhibition specifique de la voie vesiculaire de production de glucose ameliore le controle glycemique et le stockage des reserves energetiques en conditions pathologique et physiologique. Cette voie pourrait representer une nouvelle cible therapeutique dans la prevention du diabete de type 2.

International audience; The excessive endogenous glucose production (EGP) induced by glucagon participates in the development of type 2 diabetes. To further understand this hormonal control, we studied the short-term regulation by cyclic adenosine monophosphate (cAMP) of the glucose-6-phosphatase (G6Pase) enzyme, which catalyzes the last reaction of EGP. In gluconeogenic cell models, a 1-h treatment by the adenylate cyclase activator forskolin increased G6Pase activity and glucose production independently of any change in enzyme protein amount or G6P content. Using specific inhibitors or protein overexpression, we showed that the stimulation of G6Pase activity involved the protein kinase A (PKA). Results of site-directed mutagenesis, mass spectrometry analyses, and in vitro phosphorylation experiments suggested that the PKA stimulation of G6Pase activity did not depend on a direct phosphorylation of the enzyme. However, the temperature-dependent induction of both G6Pase activity and glucose release suggested a membrane-based mechanism. G6Pase is composed of a G6P transporter (G6PT) and a catalytic unit (G6PC). Surprisingly, we demonstrated that the increase in G6PT activity was required for the stimulation of G6Pase activity by forskolin. Our data demonstrate the existence of a post-translational mechanism that regulates G6Pase activity and reveal the key role of G6PT in the hormonal regulation of G6Pase activity and of EGP.Erratum inCorrection to "Post-Translational Regulation of the Glucose-6-Phosphatase Complex by Cyclic Adenosine Monophosphate Is a Crucial Determinant of Endogenous Glucose Production and Is Controlled by the Glucose-6-Phosphate Transporter". [J Proteome Res. 2016]PMID: 27111186 DOI: 10.1021/acs.jproteome.6b00284

La croissance post-natale est dependante des apports energetiques et des facteurs de croissance constituant l’axe somatotrope. Le microbiote intestinal, via sa production d’acides gras a courtes chaines, a recemment ete implique dans la regulation de la croissance chez les nouveau-nes. Chez l’adulte, les acides gras a courtes chaines ameliorent l’homeostasie energetique par induction de la neoglucogenese intestinale (NGI). Cette fonction presentant un pic d’induction 7 jours apres la naissance, nous avons teste si le pic neonatal de NGI pouvait affecter la croissance. Nous avons suivi le poids, la taille des tibias et dose l’expression genique et proteique du facteur de croissance Insuline-like-growth-factor-1 (IGF-1) et de son transporteur IGF-binding-protein-3 (IGFBP-3) chez des souris invalidees pour la NGI au 1er (I-G6pc−/−.P1) ou 12e jour post-natal (I-G6pc−/−.P12). A 8 jours, les souris I-G6pc−/−.P1 presentent une concentration plasmatique d’IGF1 et une expression hepatique d’Igf1 et d’Igfbp3 reduites de 40 % (p

Introduction Le tamoxifene est un modulateur selectif des recepteurs des œstrogenes utilise comme traitement du cancer du sein. Parallelement, il est l’activateur specifique de la recombinase Cre-ERT2, outil permettant un controle temporel tissu-specifique de la mutagenese somatique dans les modeles transgeniques. Des etudes integrant developpement et metabolisme requierent une modification genique induite par une administration de tamoxifene des la naissance. Ici, nous presentons les effets propres de l’administration neonatale de tamoxifene sur l’homeostasie energetique. Methodes Des souris C57BL/6 J mâles et femelles ont eu une injection de tamoxifene ou de son vehicule 1 jour apres la naissance, puis a l’âge adulte ont ete soumises a un regime riche en gras et en sucres pendant 1 mois. L’homeostasie glucidique a ete etudiee par des tests de tolerance au glucose et a l’insuline, la composition corporelle par imagerie par resonance magnetique, et la prise alimentaire, la depense energetique et l’activite physique ont ete mesurees en cages calorimetriques. Resultats L’administration neonatale de tamoxifene est associee, chez les mâles, a une protection de l’obesite et a une meilleure tolerance au glucose et a l’insuline. Chez les femelles, elle est associee a une augmentation de la prise de poids et de masse grasse, a une intolerance au glucose et a l’insuline, a une augmentation de la prise alimentaire et une diminution de la depense energetique. Discussion L’administration neonatale de tamoxifene exerce une forte influence sur l’homeostasie energetique. Cette influence differe en fonction du sexe, et pourrait etre due a un role specifique des hormones sexuelles.

International audience; Intestinal gluconeogenesis is a recently identified function influencing energy homeostasis. Intestinal gluconeogenesis induced by specific nutrients releases glucose, which is sensed by the nervous system surrounding the portal vein. This initiates a signal positively influencing parameters involved in glucose control and energy management controlled by the brain. This knowledge has extended our vision of the gut-brain axis, classically ascribed to gastrointestinal hormones. Our work raises several questions relating to the conditions under which intestinal gluconeogenesis proceeds and may provide its metabolic benefits. It also leads to questions on the advantage conferred by its conservation through a process of natural selection.

Introduction Malignant mesothelioma is a deadly disease that is strongly associated with asbestos exposure. Peritoneal mesotheliomas account for 10% of all the cases. BRCA1 associated protein 1 (BAP1) is a deubiquitinating hydrolase that plays a key role in various cellular processes. Germline and somatic inactivation of BRCA1 associated protein 1 gene ( BAP1 ) is frequent in pleural mesothelioma; however, little is known about its status in peritoneal mesothelioma. Methods Taking advantage of the extensive French National Network for the Diagnosis of Malignant Pleural Mesothelioma and Rare Peritoneal Tumors and the French National Network for the Treatment of Rare Peritoneal Surface Malignancies, we collected biological material and clinical and epidemiological data for 46 patients with peritoneal mesothelioma. The status of BAP1 was evaluated at the mutational and protein expression levels and combined with our previous data on copy number alterations assessed in the same samples. Results We detected mutations in 32% of the malignant peritoneal mesotheliomas analyzed. In addition, we have previously reported that copy number losses occurred in 42% of the samples included in this series. Overall, 73% of the malignant peritoneal mesotheliomas analyzed carried at least one inactivated BAP1 allele, but only 57% had a complete loss of its protein nuclear expression. Better overall survival was observed for patients with BAP1 mutations ( p = 0.04), protein expression loss ( p = 0.016), or at least one of these alterations ( p = 0.007) independently of tumor histological subtype, age, and sex. Conclusions As in pleural mesothelioma, inactivation of BAP1 is frequent in peritoneal mesotheliomas. We found that BAP1 protein nuclear expression is a good prognostic factor and a more reliable marker for the complete loss of BAP1 activity than mutation or copy number loss.

Roux-en-Y gastric bypass (RYGB) induces remission or substantial improvement of type 2 diabetes mellitus (T2D) but underlying mechanisms are still unclear. The beneficial effects of dietary proteins on energy and glucose homeostasis are mediated by the antagonist effects of peptides toward mu-opioid receptors (MORs), which are highly expressed in the distal gut. We hypothesized that the beneficial effects of RYGB could depend at least in part on the interaction of peptides from food with intestinal MORs. Duodenal-jejunal bypass (DJB) was performed in obese and lean wild-type (WT) or MOR deficient (MOR−/−) mice. Food intake and body weight was monitored daily during 3 weeks. Glucose homeostasis was assessed from glucose and insulin tolerance tests. In obese WT and MOR−/− mice, DJB induced a rapid and sustained weight loss partly independent of food intake, and a rapid improvement in glycaemic parameters. Weight loss was a major determinant of the improvements observed. In lean WT and MOR−/− mice, DJB had no effect on weight loss but significantly enhanced glucose tolerance. We found that MORs are not essential in the metabolic beneficial effects of DJB, suggesting that protein sensing in the distal gut is not a link in the metabolic benefits of gastric surgery.

International audience; The maintenance of plasma glucose is a vital necessity in all situations. Multiple adaptations permitting endogenous glucose production from the liver, kidneys, and gut take place during starvation. The mobilization of liver glycogen stores is the more rapid process to tune blood glucose from the moment where glucose availability from food starts to lack. Increased lipolysis from the adipose depots plays a crucial role to provide energy to the whole body and especially to allow the liver to carry out gluconeogenesis from lactate and alanine, which is an endergonic process. Proteolysis from skeletal muscles then supplies carbon skeletons to build glucose from amino acids released in blood. Among the exquisite late adaptations of gluconeogenesis taking place after the exhaustion of liver glycogen stores, the progressive replacement of hepatic gluconeogenesis by renal and intestinal gluconeogenesis (from glutamine) is essential, since it permits to maintain plasma glucose and in the same time to preserve energy balance of the body. Gluconeogenesis from glutamine, indeed, is an exergonic process. The late blunting in hepatic GNG paralleling the increase in intestinal GNG in late starvation allows the liver to store glycogen again, which might be a key adaptation for survival.

Patients with glycogen storage diseases type 1 (GSD1) suffer from life-threatening hypoglycaemia, when left untreated. Despite an intensive dietary treatment, patients develop severe complications, such as liver tumors and renal failure, with aging. Until now, the animal models available for studying the GSD1 did not survive after weaning. To gain further insights into the molecular mechanisms of the disease and to evaluate potential treatment strategies, we have recently developed novel mouse models in which the catalytic subunit of glucose-6 phosphatase (G6pc) is deleted in each glucose-producing organ specifically. For that, B6.G6pc(ex3lox/ex3lox) mice were crossed with transgenic mice expressing a recombinase under the control of the serum albumin, the kidney androgen protein or the villin promoter, in order to obtain liver, kidney or intestine G6pc(-/-) mice, respectively. As opposed to total G6pc knockout mice, tissue-specific G6pc deficiency allows mice to maintain their blood glucose by inducing glucose production in the other gluconeogenic organs. Even though it is considered that glucose is produced mainly by the liver, liver G6pc(-/-) mice are perfectly viable and exhibit the same hepatic pathological features as GSD1 patients, including the late development of hepatocellular adenomas and carcinomas. Interestingly, renal G6pc(-/-) mice developed renal symptoms similar to the early human GSD1 nephropathy. This includes glycogen overload that leads to nephromegaly and morphological and functional alterations in the kidneys. Thus, our data suggest that renal G6Pase deficiency per se is sufficient to induce the renal pathology of GSD1. Therefore, these new mouse models should allow us to improve the strategies of treatment on both nutritional and pharmacological points of view.

Mu-opioid receptors (MORs) are known to influence food intake at the brain level, through their involvement in the food reward system. MOR agonists stimulate food intake. On the other hand, MOR antagonists suppress food intake. MORs are also active in peripheral organs, especially in the small intestine where they control the gut motility. Recently, an indirect role in the control of food intake was ascribed to MORs in the extrinsic gastrointestinal neural system. MORs present in the neurons of the portal vein walls sense blood peptides released from the digestion of dietary protein. These peptides behave as MOR antagonists. Their MOR antagonist action initiates a gut-brain circuitry resulting in the induction of intestinal gluconeogenesis, a function controlling food intake. Thus, periportal MORs are a key mechanistic link in the satiety effect of protein-enriched diets.

Scientific Reports 6: Article number: 20127; published online: 16 February 2016; updated: 20 April 2016. The original version of this Article contained an error in the spelling of the author Maha Al-Asmakh, which was incorrectly given as Al-Asmakh Maha. This has now been corrected in the PDF and HTML versions of the Article.

The liver is a key organ of metabolic homeostasis with functions that oscillate in response to food intake. Although liver and gut microbiome crosstalk has been reported, microbiome-mediated effects on peripheral circadian clocks and their output genes are less well known. Here, we report that germ-free (GF) mice display altered daily oscillation of clock gene expression with a concomitant change in the expression of clock output regulators. Mice exposed to microbes typically exhibit characterized activities of nuclear receptors, some of which (PPARα, LXRβ) regulate specific liver gene expression networks, but these activities are profoundly changed in GF mice. These alterations in microbiome-sensitive gene expression patterns are associated with daily alterations in lipid, glucose, and xenobiotic metabolism, protein turnover, and redox balance, as revealed by hepatic metabolome analyses. Moreover, at the systemic level, daily changes in the abundance of biomarkers such as HDL cholesterol, free fatty acids, FGF21, bilirubin, and lactate depend on the microbiome. Altogether, our results indicate that the microbiome is required for integration of liver clock oscillations that tune output activators and their effectors, thereby regulating metabolic gene expression for optimal liver function. Région Midi-Pyrénées to HG (Mathusalem) and to WW (Chaire d’Excellence Pierre de Fermat). This work was also supported by grants from the Swiss National Science Foundation (individual grants to WW), the Bonizzi-Theler-Stiftung (WW), the 7th EU program TORNADO (WW, SP), and by the Etat de Vaud and the Lee Kong Chian School of Medicine, Nanyang Technological University Start-Up Grants. SP is also supported by grants from the Merieux Foundation, Swedish Medical Research Council, the SCELCE Microbiome Centre at NTU, Singapore, and CIFAR Institute, Canada.

Despite the strong correlation between non-alcoholic fatty liver disease and insulin resistance, hepatic steatosis is associated with greater whole-body insulin sensitivity in several models. We previously reported that the inhibition of hepatic glucose production (HGP) protects against the development of obesity and diabetes despite severe steatosis, thanks to the secretion of specific hepatokines such as fibroblast growth factor 21 (FGF21) and angiopoietin-related growth factor. In this work, we focused on adipose tissue to assess whether liver metabolic fluxes might, by interorgan communication, control insulin signalling in lean animals. Insulin signalling was studied in the adipose tissue of mice lacking the catalytic subunit of glucose 6-phosphatase, the key enzyme in endogenous glucose production, in the liver (L-G6pc (-/-) mice). Morphological and metabolic changes in the adipose tissues were characterised by histological analyses, gene expression and protein content. Mice lacking HGP exhibited improved insulin sensitivity of the phosphoinositide 3-kinase/Akt pathway in the subcutaneous adipose tissue associated with a browning of adipocytes. The suppression of HGP increased FGF21 levels in lean animals, and increased FGF21 was responsible for the metabolic changes in the subcutaneous adipose tissue but not for its greater insulin sensitivity. The latter might be linked to an increase in the ratio of monounsaturated to saturated fatty acids released by the liver. Our work provides evidence that HGP controls subcutaneous adipose tissue browning and insulin sensitivity through two pathways: the release of beneficial hepatokines and changes in hepatic fatty acids profile.

OBJECTIVE Since the pioneering work of Claude Bernard, the scientific community has considered the liver to be the major source of endogenous glucose production in all postabsorptive situations. Nevertheless, the kidneys and intestine can also produce glucose in blood, particularly during fasting and under protein feeding. The aim of this study was to better define the importance of the three gluconeogenic organs in glucose homeostasis. RESEARCH DESIGN AND METHODS We investigated blood glucose regulation during fasting in a mouse model of inducible liver-specific deletion of the glucose-6-phosphatase gene (L-G6pc−/− mice), encoding a mandatory enzyme for glucose production. Furthermore, we characterized molecular mechanisms underlying expression changes of gluconeogenic genes (G6pc, Pck1, and glutaminase) in both the kidneys and intestine. RESULTS We show that the absence of hepatic glucose release had no major effect on the control of fasting plasma glucose concentration. Instead, compensatory induction of gluconeogenesis occurred in the kidneys and intestine, driven by glucagon, glucocorticoids, and acidosis. Moreover, the extrahepatic action of glucagon took place in wild-type mice. CONCLUSIONS Our study provides a definitive quantitative estimate of the capacity of extrahepatic gluconeogenesis to sustain fasting endogenous glucose production under the control of glucagon, regardless of the contribution of the liver. Thus, the current dogma relating to the respective role of the liver and of extrahepatic gluconeogenic organs in glucose homeostasis requires re-examination.

Intestinal gluconeogenesis (IGN) promotes metabolic benefits through activation of a gut-brain neural axis. However, the local mediator activating gluconeogenic genes in the enterocytes remains unknown. We show that (i) vasoactive intestinal peptide (VIP) signaling through VPAC1 receptor activates the intestinal glucose-6-phosphatase gene in vivo, (ii) the activation of IGN by propionate is counteracted by VPAC1 antagonism, and (iii) VIP-positive intrinsic neurons in the submucosal plexus are increased under the action of propionate. These data support the role of VIP as a local neuromodulator released by intrinsic enteric neurons and responsible for the induction of IGN through a VPAC1 receptor-dependent mechanism in enterocytes.

The liver is considered the main contributor of endogenous glucose production (EGP) in the postabsorptive (PA) state in mammals. However, it has been shown that the kidney, in PA and fasting states, and the intestine, in insulinopenia states, could make significant contributions to EGP. Using glucose tracer dilution combined to a vessel ligaturing approach, we studied the respective role of these organs in glucose turnover under various nutritional conditions in the rat (Rattus norvegicus). Both organs constitute key sites of glucose disposal in all situations in the non-moving rat. The kidney makes a small (12%) contribution to EGP in the PA state (9.6+/-1.3 micromol/kg min, means+/-SEM, n=5), which is dramatically increased (p

The increasing worldwide prevalence of obesity and its commonly associated disease type 2 diabetes has a dramatic influence on morbidity and mortality in the human population [1]. Among currently available obesity treatments, bariatric surgery achieves the best substantial and permanent weight loss [1]. Interestingly, surgeries inducing a rapid reduction in appetite and a normalization of glycemic index (e.g. Roux-en-Y gastric bypass) are notably associated with an increase in the anorexigenic gut peptides PYY and GLP-1 [1]. These two hormones act as peripheral sensory inputs integrated by the central nervous system (CNS) to modulate appetite and energy expenditure. The pharmacological mimicry of the hormonal milieu after bariatric surgery has thus been proposed as a potential strategy for the treatment of obesity [1]. However, such therapies will require a complete understanding of the mechanisms by which gut hormonal signals interact and integrate with other peripheral and central informations to modulate appetite. PYY is an amidated peptide of 36-amino acids composed of tyrosine residues (Y) at each end. PYY is highly homologous to another gut hormone (pancreatic polypeptide) and to the central neurotransmitter NPY. Whereas PYY1-36 is an agonist of three mammalian NPY receptors (Y1, 2 and 5), PYY3-36, resulting from the digestion of PYY1-36 by the enzyme dipeptidyl peptidase 4 (DPP-4) is a selective Y2 receptor (Y2R) agonist. PYY is synthesized after the meal by the L endocrine cells of the small intestine in proportion to energy intake. The anorectic effect of PYY is specifically mediated by Y2R via interactions with both the vagus nerve and the arcuate nucleus of the hypothalamus [2]. In animals and humans, intravenous infusion of PYY3-36 reduces food intake in both lean and obese individuals [3]. Whereas the role of PYY3-36 in appetite control has been well characterized, its role in glucose homeostasis remains controversial. In this issue, Chandarana and colleagues address the role of peripheral PYY on glucose homeostasis, including the context of bariatric surgery in mice [4]. The administration of PYY3-36 during an intraperitoneal glucose tolerance test (IPGTT) had a lowering effect on glycemia, which depended on Y2R. On the contrary, PYY1-36 administration had no effect. Moreover, the lowering effect of peripheral PYY3-36 on glycemia was not inhibited by the central administration of an Y2R antagonist, but only by the peripheral (IP) injection of such an antagonist. The lowering effect of PYY3-36 on glycemia occurred in parallel to an increase in blood insulin levels. However, whilst PYY1-36 had an inhibitory effect on insulin secretion as already described, PYY3-36 had no direct effect on insulin secretion. Interestingly, exogenous PYY3-36 decreased blood glucose levels only in a postprandial context. This is in line with the fact that endogenous PYY is secreted in response to lipids or glucose by intestinal L-cells [1]. The authors thus hypothesized that the postprandial increase in PYY levels measured in the portal vein after a meal could have a role in regulating postprandial insulin secretion via an incretin effect. Enterogastric anastomosis (EGA) performed in obese mice is an operation that mimics RYGBP surgery in humans [5]. The authors used this model to decipher the effect of PYY3-36 on glucose homeostasis. In wild-type EGA mice, the increase in PYY3-36 paralleled an increase in GLP-1. This was abrogated in PYY null mice. This suggested that PYY3-36 might regulate GLP-1 secretion. Accordingly, the authors showed that PYY3-36 enhanced glucose-stimulated and meal-stimulated GLP-1 secretion in the portal vein of control mice. Moreover, this effect was dependent on peripheral Y2R receptors. The use of exendin 9-39, an antagonist of GLP-1 receptor, confirmed that the positive effect of PYY3-36 on glucose homeostasis was, at least in part, due to GLP-1 action. The main interest of these findings is that they complement previous studies on the importance of intestinal signals in glucose homeostasis by providing a new link dealing with the regulation of insulin secretion by PYY. The authors first showed that PYY3-36 controlled glucose homeostasis though a regulation of insulin secretion and secondly that this regulation is independent of central Y2R. On the contrary, the anorectic action of peripheral administration of PYY3-36 has been shown to be dependent on brain Y2R [6]. The highly interesting point of this study concerns the link between the two gut hormones PYY3-36 and GLP-1. Data from Chandarana and colleagues suggest that PYY3-36 improves insulin secretion after a meal in a GLP-1 dependent manner (Figure 1). However, a perceived weakness is the lack of a comprehensive cellular mechanism linking the secretions of both hormones. Future studies will have to decipher this mechanism. Important questions remain unresolved. For example, does PYY3-36 act directly on Y2R present in intestinal L-cells to induce and/or improve GLP-1 secretion? Does PYY3-36 act on Y2R via the autonomous nervous system, which is very dense within the walls of the portal vein [7], to stimulate GLP-1 secretion? Is there a role in this chain of the central nervous system via a reflex arc? It is noteworthy that a neural mechanism has been suggested to account at least in part for the anorectic effect of PYY3-36 [2] or for the benefits of GLP-1 on glucose control [8,9]. Moreover, it is concerning that the interplay between PYY, GLP-1 and Y2R may be complicated by the possible involvement of DPP-4. Indeed, PYY3-36 is produced from the digestion of PYY1-36 by DPP-4. The data reported in this study suggested that PYY3-36 improves glucose homeostasis, whilst PYY1-36 does not. Thus, DPP-4 inhibitors, which are currently used as a treatment to prolong the GLP-1 incretin effect in type-2-diabetes patients, might oppose rather than contribute to the PYY3-36 positive effect. If the mechanism suggested here were of primary importance, it would be hardly reconcilable with the benefits of DDP-4 inhibitors on GLP-1 incretin effects in pathophysiological situations [10]. Figure 1 PYY3-36 improves insulin secretion after a meal in a GLP-1 dependent manner. The results obtained by Chandarana et al. are illustrated in orange (arrows): meal/glucose increase the levels of PYY3-36 in blood. PYY3-36, via the activation of peripheral ... In the obesity and diabetes field, it is obvious that implementing the knowledge on the peripheral effects of PYY3-36 could represent an important step in the understanding of the complex interplay between gut hormones, their maturation processes and their roles in regulating glucose and energy homeostasis. Further research in this field is warranted, since it may provide novel paradigms that could be useful in the elaboration of future approaches of prevention and/or treatment of metabolic diseases.

Glucose-6-phosphatase (Glc6Pase), the last enzyme of gluconeogenesis, is only expressed in the liver, kidney and small intestine. The expression of the Glc6Pase gene exhibits marked specificities in the three tissues in various situations, but the molecular basis of the tissue specificity is not known. The presence of a consensus binding site of CDX proteins in the minimal Glc6Pase gene promoter has led us to consider the hypothesis that these intestine-specific CDX factors could be involved in the Glc6Pase-specific expression in the small intestine. We first show that the Glc6Pase promoter is active in both hepatic HepG2 and intestinal CaCo2 cells. Using gel shift mobility assay, mutagenesis and competition experiments, we show that both CDX1 and CDX2 can bind the minimal promoter, but only CDX1 can transactivate it. Consistently, intestinal IEC6 cells stably overexpressing CDX1 exhibit induced expression of the Glc6Pase protein. We demonstrate that a TATAAAA sequence, located in position –31/–25 relating to the transcription start site, exhibits separable functions in the preinitiation of transcription and the transactivation by CDX1. Disruption of this site dramatically suppresses both basal transcription and the CDX1 effect. The latter may be restored by inserting a couple of CDX- binding sites in opposite orientation similar to that found in the sucrase-isomaltase promoter. We also report that the specific stimulatory effect of CDX1 on the Glc6Pase TATA-box, compared to CDX2, is related to the fact that CDX1, but not CDX2, can interact with the TATA-binding protein. Together, these data strongly suggest that CDX proteins could play a crucial role in the specific expression of the Glc6Pase gene in the small intestine. They also suggest that CDX transactivation might be essential for intestine gene expression, irrespective of the presence of a functional TATA box.

International audience; ABSTRACTType 2 diabetes is characterized by a deterioration of glucose tolerance, which associates insulinresistance of glucose uptake by peripheral tissues and increased endogenous glucose production.Here we report that the specific suppression of hepatic glucose production positively modulateswhole-body glucose and energy metabolism. We used mice deficient in liver glucose-6 phosphatasethat is mandatory for endogenous glucose production. When they were fed a high fat/high sucrosediet, they resisted the development of diabetes and obesity due to the activation of peripheralglucose metabolism and thermogenesis. This was linked to the secretion of hepatic hormones likefibroblast growth factor 21 and angiopoietin-like factor 6. Interestingly, the deletion of hepaticglucose-6 phosphatase in previously obese and insulin-resistant mice resulted in the rapidrestoration of glucose and body weight controls. Therefore, hepatic glucose production is anessential lever for the control of whole-body energy metabolism during the development of obesityand diabetes.

It is long known that the gut can contribute to the control of glucose homeostasis via its high glucose utilization capacity. Recently, a novel function in intestinal glucose metabolism (gluconeogenesis) was described. The intestine notably contributes to about 20-25% of total endogenous glucose production during fasting. More importantly, intestinal gluconeogenesis is capable of regulating energy homeostasis through a communication with the brain. The periportal neural system senses glucose (produced by intestinal gluconeogenesis) in the portal vein walls, which sends a signal to the brain to modulate hunger sensations and whole body glucose homeostasis. Relating to the mechanism of glucose sensing, the role of the glucose receptor SGLT3 has been strongly suggested. Moreover, dietary proteins mobilize intestinal gluconeogenesis as a mandatory link between their detection in the portal vein and their effect of satiety. In the same manner, dietary soluble fibers exert their anti-obesity and anti-diabetic effects via the induction of intestinal gluconeogenesis. FFAR3 is a key neural receptor involved in the specific sensing of propionate to activate a gut-brain reflex arc triggering the induction of the gut gluconeogenic function. Lastly, intestinal gluconeogenesis might also be involved in the rapid metabolic improvements induced by gastric bypass surgeries of obesity.