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International audience; Glycogen Storage Disease Type I (GSDI) is an inherited disease caused by glucose-6 phosphatase (G6Pase) deficiency, leading to a loss of endogenous glucose production and severe hypoglycemia. Moreover, most GSDI patients develop a chronic kidney disease (CKD) due to lipid accumulation in the kidney. Similar to diabetic CKD, activation of renin-angiotensin system (RAS) promotes renal fibrosis in GSDI. Here, we investigated the physiological and molecular effects of RAS blockers in GSDI patients and mice. A retrospective analysis of renal function was performed in 21 GSDI patients treated with RAS blockers. Cellular and metabolic impacts of RAS blockade were analyzed in K.G6pc−/− mice characterized by G6pc1 deletion in kidneys. GSDI patients started RAS blocker treatment at a median age of 21 years and long-term treatment reduced the progression of CKD in about 50% of patients. However, CKD progressed to kidney failure in 20% of treated patients, requiring renal transplantation. In K.G6pc−/− mice, CKD was associated with an impairment of autophagy and ER stress. RAS blockade resulted in a rescue of autophagy and decreased ER stress, concomitantly with decreased fibrosis and improved renal function, but without impact on glycogen and lipid contents. In conclusion, these data confirm the partial beneficial effect of RAS blockers in the prevention of CKD in GSDI. Mechanistically, we show that these effects are linked to a reduction of cell stress, without affecting metabolism.

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.

Objective Roux-en-Y gastric surgery (RYGB) promotes a rapid and sustained weight loss and amelioration of glucose control in obese patients. A high number of molecular hypotheses were previously tested using duodenal-jejunal bypass (DJB) performed in various genetic models of mice with knockouts for various hormones or receptors. The data were globally negative or inconsistent. Therefore, the mechanisms remained elusive. Intestinal gluconeogenesis is a gut function that has been suggested to contribute to the metabolic benefits of RYGB in obese patients. Methods We studied the effects of DJB on body weight and glucose control in obese mice fed a high fat-high sucrose diet. Wild type mice and mice with a genetic suppression of intestinal gluconeogenesis were studied in parallel using glucose- and insulin-tolerance tests. Fecal losses, including excretion of lipids, were studied from the feces recovered in metabolic cages. Results DJB induced a dramatic decrease in body weight and improvement in glucose control (glucose- and insulin-tolerance) in obese wild type mice fed a high calorie diet, for 25 days after the surgery. The DJB-induced decrease in food intake was transient and resumed to normal in 7–8 days, suggesting that decreased food intake could not account for the benefits. Total fecal losses were about 5 times and lipid losses 7 times higher in DJB-mice than in control (sham-operated and pair-fed) mice, and could account for the weight loss of mice. The results were comparable in mice with suppression of intestinal gluconeogenesis. There was no effect of DJB on food intake, body weight or fecal loss in lean mice fed a normal chow diet. Conclusions DJB in obese mice fed a high calorie diet promotes dramatic fecal loss, which could account for the dramatic weight loss and metabolic benefits observed. This could dominate the effects of the mouse genotype/phenotype. Thus, fecal energy loss should be considered as an essential process contributing to the metabolic benefits of DJB in obese mice., Highlights • Duodenal-jejunal bypass (DJB) promotes weight loss in mice fed a high calorie diet. • DJB induces dramatic fecal energy losses in mice fed a high calorie diet. • DJB has no effect in mice fed a control (starch-based) diet. • There is no fecal losses in DJB-mice fed a control diet. • Fecal energy loss is a cause of body weight loss in DJB-mice fed high calorie diet.

International audience; Glycogen storage disease type I (GSDI) is a rare metabolic disease due to glucose-6 phosphatase deficiency, characterized by fasting hypoglycemia. Patients also develop chronic kidney disease whose mechanisms are poorly understood. To decipher the process, we generated mice with a kidney-specific knockout of glucose-6 phosphatase (K.G6pc-/- mice) that exhibited the first signs of GSDI nephropathy after 6 months of G6pc deletion. We studied the natural course of renal deterioration in K.G6pc-/- mice for 18 months and observed the progressive deterioration of renal functions characterized by early tubular dysfunction and a later destruction of the glomerular filtration barrier. After 15 months, K.G6pc-/- mice developed tubular-glomerular fibrosis and podocyte injury, leading to the development of cysts and renal failure. On the basis of these findings, we were able to detect the development of cysts in 7 out of 32 GSDI patients, who developed advanced renal impairment. Of these 7 patients, 3 developed renal failure. In addition, no renal cysts were detected in six patients who showed early renal impairment. In conclusion, renal pathology in GSDI is characterized by progressive tubular dysfunction and the development of polycystic kidneys that probably leads to the development of irreversible renal failure in the late stages. Systematic observations of cyst development by kidney imaging should improve the evaluation of the disease's progression, independently of biochemical markers.

International audience; MINI-ABSTRACTWe performed bile diversions matching the modified biliary flow occurring after gastric bypass (GBP)in rats. Our results strongly suggest that the only modification of bile routing mimics the mainmetabolic benefits of GBP: 1) improved glucose control, 2) decreased food intake because ofdisinterest in high calorie food.STRUCTURED ABSTRACTObjective: To evaluate the role of bile routing modification on the beneficial effects of gastric bypasssurgery on glucose and energy metabolism.Summary background data: Gastric bypass surgery (GBP) promotes early improvements in glucoseand energy homeostasis in obese diabetic patients. A suggested mechanism associates a decrease inhepatic glucose production (HGP) to an enhanced intestinal gluconeogenesis (IGN). Moreover,plasma bile acids are elevated after GBP and bile acids are inhibitors of gluconeogenesis.Methods: In male Sprague-Dawley rats, we performed bile diversions from the bile duct to the midjejunumor the mid-ileum to match the modified bile delivery in the gut occurring in GBP. Bodyweight, food intake, glucose tolerance, insulin sensitivity and food preference were analyzed. Theexpression of gluconeogenesis genes was evaluated in both the liver and the intestine.Results: Bile diversions mimicking GBP promote an increase in plasma bile acids and a markedimprovement in glucose control. Bile bioavailability modification is causal since a bile acidsequestrant suppresses the beneficial effects of bile diversions on glucose control. In agreement withthe inhibitory role of bile acids on gluconeogenesis, bile diversions promote a blunting in HGP,whereas IGN is increased in the gut segments devoid of bile. In rats fed a high fat-high sucrose diet,bile diversions improve glucose control and dramatically decrease food intake due to an acquireddisinterest in fatty food.Conclusion: This study shows that bile routing modification is a key mechanistic feature in thebeneficial outcomes of GBP.

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; Background Leucine supplementation might have therapeutic potential in preventing diet-induced obesity and improving insulin sensitivity. However, the underlying mechanisms are at present unclear. Additionally, it is unclear whether leucine supplementation might be equally efficacious once obesity has developed. Methodology/Principal Findings Male C57BL/6J mice were fed chow or a high-fat diet (HFD), supplemented or not with leucine for 17 weeks. Another group of HFD-fed mice (HFD-pairfat group) was food restricted in order to reach an adiposity level comparable to that of HFD-Leu mice. Finally, a third group of mice was exposed to HFD for 12 weeks before being chronically supplemented with leucine. Leucine supplementation in HFD-fed mice decreased body weight and fat mass by increasing energy expenditure, fatty acid oxidation and locomotor activity in vivo. The decreased adiposity in HFD-Leu mice was associated with increased expression of uncoupling protein 3 (UCP-3) in the brown adipose tissue, better insulin sensitivity, increased intestinal gluconeogenesis and preservation of islets of Langerhans histomorphology and function. HFD-pairfat mice had a comparable improvement in insulin sensitivity, without changes in islets physiology or intestinal gluconeogenesis. Remarkably, both HFD-Leu and HFD-pairfat mice had decreased hepatic lipid content, which likely helped improve insulin sensitivity. In contrast, when leucine was supplemented to already obese animals, no changes in body weight, body composition or glucose metabolism were observed. Conclusions/Significance These findings suggest that leucine improves insulin sensitivity in HFD-fed mice by primarily decreasing adiposity, rather than directly acting on peripheral target organs. However, beneficial effects of leucine on intestinal gluconeogenesis and islets of Langerhans's physiology might help prevent type 2 diabetes development. Differently, metabolic benefit of leucine supplementation is lacking in already obese animals, a phenomenon possibly related to the extent of the obesity before starting the supplementation.

International audience; The detection of glucose in the hepatoportal area is a simple but crucial peripheral cue initiating a nervous signal that ultimately leads to a wide array of metabolic and behavioural responses, such as decreased food intake, tighter control of glucose homeostasis, or appearance of food preference. This signal has been suggested to mediate the effects of high-protein diets, as opposed to high-fat/high-sucrose diets. Nevertheless, the central targets of the signal originating from the hepatoportal area remain largely undocumented. Using immunohistochemistry on the brain of male rats, we show here that portal glucose increases c-Fos expression in the brainstem, in the hypothalamus (in particular in neurons expressing pro-opiomelanocortin) and also in olfactory and other limbic and cortical areas, including those functionally implicated in reward (Experiment 1). In similar postabsorptive conditions, a high-protein diet induced similar effects in the hypothalamus and the granular cells of the main olfactory bulb, whereas the high-fat/high-sucrose diet actually reduced the basal expression of c-Fos in cortical layers. Both diets also decreased the number of neurons expressing c-Fos in the amygdala and gustatory areas (Experiment 2). Altogether, these findings suggest that the peripheral signal primed by portal glucose sensing may influence behavioural adaptation such as food preference via a network including the olfactory pathway, central amygdala, nucleus accumbens and orbitofrontal cortex, in addition to satiety and metabolic effects primarily implicating the hypothalamic response.

International audience; Unlike the adjustable gastric banding procedure (AGB), Roux-en-Y gastric bypass surgery (RYGBP) in humans has an intriguing effect: a rapid and substantial control of type 2 diabetes mellitus (T2DM). We performed gastric lap-band (GLB) and entero-gastro anastomosis (EGA) procedures in C57Bl6 mice that were fed a high-fat diet. The EGA procedure specifically reduced food intake and increased insulin sensitivity as measured by endogenous glucose production. Intestinal gluconeogenesis increased after the EGA procedure, but not after gastric banding. All EGA effects were abolished in GLUT-2 knockout mice and in mice with portal vein denervation. We thus provide mechanistic evidence that the beneficial effects of the EGA procedure on food intake and glucose homeostasis involve intestinal gluconeogenesis and its detection via a GLUT-2 and hepatoportal sensor pathway.

International audience; Beneficial effects of dietary fiber on glucose and energy homeostasis have long been described, focusing mostly on the production of short-chain fatty acids by the gut commensal bacteria. However, bacterial fermentation of dietary fiber also produces large amounts of succinate and, to date, no study has focused on the role of succinate on host metabolism. Here, we fed mice a fiber-rich diet and found that succinate was the most abundant carboxylic acid in the cecum. Dietary succinate was identified as a substrate for intestinal gluconeogenesis (IGN), a process that improves glucose homeostasis. Accordingly, dietary succinate improved glucose and insulin tolerance in wild-type mice, but those effects were absent in mice deficient in IGN. Conventional mice colonized with the succinate producer Prevotella copri exhibited metabolic benefits, which could be related to succinate-activated IGN. Thus, microbiota-produced succinate is a previously unsuspected bacterial metabolite improving glycemic control through activation of IGN.

Introduction La nephropathie des patients atteints de glycogenose de type 1 [maladie rare due a une deficience de la glucose-6 phosphatase (G6Pase)] est[CHECKPAGE]] tres similaire a celle observee chez les diabetiques de type 1 ou de type 2. Au niveau moleculaire, elle se caracterise par une accumulation de glucose-6 phosphate, l’activation de la lipogenese de novo et du systeme renine-angiotensine, qui menent au developpement d’une fibrose. Disposant d’un modele murin d’invalidation specifique de la G6Pase au niveau renal (souris K.G6pc-/-) reproduisant la pathologie renale chronique, nous avons analyse l’effet d’un regime de type « cafeteria » sur la progression de la nephropathie. Materiels et methodes Des souris K.G6pc-/- ont ete soumises a un regime standard hyperglucidique, ou un regime enrichi en graisses et en saccharose (HF/ HS) pendant 9 mois. La pathologie renale a ete evaluee par la mesure des para-metres plasmatiques et urinaires et l’analyse histologique et moleculaire des reins. Resultats Apres 9 mois de regime, l’accumulation de triglycerides dans le cortex renal est plus importante sous regime HF/HS, alors que l’accumulation de glycogene est legerement plus faible en comparaison au regime standard. Les observations en microscope electronique de transmission ont montre une destruction glomerulaire plus importante chez les souris K.G6pc-/- sous regime HF/HS. Cette alteration de la barriere de filtration se traduit par une micro-albuminurie plus importante sous regime HF/HS (114 ± 33 µg albumine/ 24 heures) par rapport au regime standard (64 ± 4 µg albumine/24 heures), l’apparition d’une proteinurie et l’accumulation d’uree dans le plasma. De plus, les souris K.G6pc-/- presentent une fibrose renale apres 9 mois de regime HF/ HS, mais pas sous regime standard. Conclusion Nos resultats mettent en evidence un role deletere des regimes « type cafeteria » sur le developpement d’une nephropathie proche de celle des diabetiques. La prise en charge nutritionnelle des patients diabetiques est donc cruciale pour ralentir le developpement de la maladie renale. Declaration d’interet Les auteurs declarent ne pas avoir d’interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Objective High-protein diets favor weight loss and its maintenance. Whether these effects might be recapitulated by certain amino acids is unknown. Therefore, the impact of leucine supplementation on energy balance and associated metabolic changes in diet-induced obese (DIO) mice during and after weight loss was investigated. Methods DIO C57BL/6J mice were fed a normocaloric diet to induce weight loss while receiving or not the amino acid leucine in drinking water. Body weight, food intake, body composition, energy expenditure, glucose tolerance, insulin, and leptin sensitivity were evaluated. Q-PCR analysis was performed on muscle, brown and white adipose tissues. Results DIO mice decreased body weight and fat mass in response to chow, but supplementation with leucine did not affect these parameters. During weight maintenance, mice supplemented with leucine had improved glucose tolerance, increased leptin sensitivity, and lower respiratory quotient. The latter was associated with changes in the expression of several genes modulating fatty acid metabolism and mitochondrial activity in the epididymal white and the brown adipose tissues, but not muscle. Conclusions Leucine supplementation might represent an adjuvant beneficial nutritional therapy during weight loss and maintenance, because it improves lipid and glucose metabolism and restores leptin sensitivity in previously obese animals.

Portal vein glucose sensors detect variations in glycemia to induce a nervous signal that influences food intake and glucose homeostasis. Previous experiments using high infusions of glucose suggested a metabolic sensing involving glucose transporter 2 (GLUT2). Here we evaluated the afferent route for the signal and candidate molecules for detecting low glucose fluxes. Common hepatic branch vagotomy did not abolish the anorectic effect of portal glucose indicating dorsal transmission. GLUT2 null mice reduced their food intake in response to portal glucose signal initiated by protein enriched diet. A similar response of Trpm5 null mice and portal infusions of sweeteners also excluded sugar taste receptors. Conversely infusions of alpha methylglucose but not 3 O methylglucose decreased food intake while phlorizin prevented the effect of glucose. This suggested sensing through SGLT3 which was expressed in the portal area. From these results we propose a finely tuned dual mechanism for portal glucose sensing that responds to different physiological conditions. © 2012 Elsevier GmbH.

International audience; Intestinal gluconeogenesis is involved in the control of food intake. We show that mu-opioid receptors (MORs) present in nerves in the portal vein walls respond to peptides to regulate a gut-brain neural circuit that controls intestinal gluconeogenesis and satiety. In vitro, peptides and protein digests behave as MOR antagonists in competition experiments. In vivo, they stimulate MOR-dependent induction of intestinal gluconeogenesis via activation of brain areas receiving inputs from gastrointestinal ascending nerves. MOR-knockout mice do not carry out intestinal gluconeogenesis in response to peptides and are insensitive to the satiety effect induced by protein-enriched diets. Portal infusions of MOR modulators have no effect on food intake in mice deficient for intestinal gluconeogenesis. Thus, the regulation of portal MORs by peptides triggering signals to and from the brain to induce intestinal gluconeogenesis are links in the satiety phenomenon associated with alimentary protein assimilation.

Introduction De nombreuses donnees suggerent des interactions entre les systemes mu-opioide et endocannabinoide dans les domaines de la nociception et de l'addiction. Les recepteurs aux mu-opioides (MOR) et aux endocannabinoides (CB1) forment des heterodimeres in vitro et in vivo et partagent des sites d'expression dans plusieurs regions du cerveau. Nous avons pu montrer 1) que les MOR periportaux modulent la prise alimentaire en induisant la neoglucogenese intestinale, fonction peripherique connue pour ses effets de satiete ; 2) que les CB1 periportaux agissaient de maniere similaire. Nous avons emis l'hypothese que les deux systemes agiraient en synergie pour controler la prise alimentaire. Materiels et methodes Des souris sauvages sont perfusees en veine porte avec des doses combinees subefficaces d'antagonistes CB1 et/ou MOR. Leur prise alimentaire et leurs neoglucogeneses intestinale et hepatique sont evaluees. Pour etudier si l'effet de satiete dependant des MOR necessite la presence des CB1, nous avons etudie la prise alimentaire et suivi le poids de souris CB1-/- nourries avec un regime hyperproteique (qui est un effecteur MOR). Resultats Des doses combinees subefficaces d'antagonistes CB1 et MOR diminuent la prise alimentaire de 50 % chez les souris sauvages alors qu'elles n'ont aucun effet lorsqu'elles sont perfusees separement. L'activite de la glucose-6 phosphatase (G6Pase) intestinale est augmentee par les doses combinees (29,0 ± 1,1 vs 18,0 ± 2,2 U/g de proteines pour le vehicule, p vs 77,2 ± 4,6 U/g pour le vehicule, p Conclusion Les recepteurs MOR et CB1 controlent de maniere synergique la prise alimentaire via la modulation d'une fonction peripherique: la neoglucogenese intestinale. Declaration d’interet Les auteurs declarent ne pas avoir d'interet direct ou indirect (financier ou en nature) avec un organisme prive, industriel ou commercial en relation avec le sujet presente.

Objectifs Les effets hypophagiques des antagonistes selectifs du recepteur aux endocannabinoides CB1 sont attribues a des mecanismes centraux. On trouve aussi des CB1 sur les fibres nerveuses innervant l’intestin. La neoglucogenese intestinale (NGI) induit la satiete et potentialise la suppression de la production hepatique de glucose (PHG) par l’insuline via un signal glucose portal. Nous avons emis l’hypothese que les CB1 peripheriques pourraient moduler la prise alimentaire en induisant la NGI. Methodes Des souris vigiles sauvages et invalidees pour le gene de la G6Pc dans l’intestin (I-G6Pc-/−) sont perfusees en veine porte avec un antagoniste des CB1 semblable au Rimonabant (AM251). Leur prise alimentaire, leur neoglucogenese intestinale et hepatique sont quantifiees. Un marquage c-Fos des noyaux hypothalamiques et des relais centraux des voies spinale et vagale a ete egalement realise. Resultats L’activite de la glucose-6 phosphatase (G6Pase) intestinale est augmentee par l’AM251 (34,8 ± 2,4 vs 19,4 ± 2,8 U/g de proteines avec le vehicule). Au contraire, l’activite G6Pase hepatique est diminuee par l’AM251 (43,7 ± 4,2 vs 60,8 ± 8,1 U/g de proteines avec le vehicule). La perfusion de l’AM251 est associee a une diminution de la prise alimentaire de 30 %. On constate une activation neuronale des centres de satiete ainsi que des relais centraux des voies spinale et vagale en reponse a l’inhibition des CB1 portaux. L’ensemble de ces effets est aboli chez les souris I-G6Pc-/− et par denervation portale (capsaicine). Discussion L’effet hypophagique et de diminution de la PHG de l’AM251 perfuse en veine porte sont dependants de l’induction d’une fonction peripherique : la NGI.

Introduction La chirurgie de l'obesite de type by-pass gastrique (BPG) a montre des effets spectaculaires dans l'amelioration, voire la remission, du diabete de type 2 independamment de la perte de poids. La neoglucogenese intestinale (NGGI) induit des effets benefiques sur l'homeostasie glucidique via l'emission d'un « signal glucose portal » a destination du cerveau. Nous avons teste l'hypothese selon laquelle les effets metaboliques benefiques du BPG pourraient dependre de la NGGI et donc ne pas prendre place chez des souris invalidees pour la glucose-6-phosphatase intestinale, l'enzyme essentielle de la neoglucogenese (I-G6pc-KO). Materiels et methodes Des BPG (sans reduction de la taille de l'estomac) et des laparotomies-sham ont ete realises sur des souris temoins (B6J) et I-G6pc-KO (n=5–6) nourries en regime standard a base d'amidon. Le poids, la prise alimentaire et les tolerances au glucose et a l'insuline ont ete etudies. Resultats Apres BPG, les souris B6J et I-G6pc-KO ingerent la meme quantite de nourriture que leurs temoins laparotomie. La sensibilite a l'insuline n'est modifiee apres BPG ni chez les souris B6J ni chez les souris I-G6pc-KO par rapport aux temoins laparotomie (aire sous la courbe : 624±36 vs 565±26 pour les B6J-BPG vs B6J-laparotomie, NS ; 780±54 vs 692±33 pour les I-G6pc-KO-BPG vs I-G6pc-KO-laparotomie, NS). Par contre, la tolerance au glucose est amelioree chez les souris B6J-BPG vs B6J-laparotomie (aire sous la courbe : 2 291±74 vs 2 588±72, p Conclusion Chez la souris en regime standard, la NGGI a un role causal dans l'amelioration de la tolerance au glucose induite par le BPG, en absence de perte de poids. Cet effet semble etre independant de la sensibilite a l'insuline.

Objectif Les effets hypophagiques des antagonistes selectifs du recepteur aux endocannabinoides CB1 (CB1R) sont attribues a des mecanismes centraux notamment hypothalamiques. On trouve aussi des CB1Rs sur les fibres nerveuses innervant le tractus gastro-intestinal. En induisant un signal glucose portal, la neoglucogenese intestinale (NGI) induit la satiete et potentialise la suppression de la production hepatique de glucose par l'insuline. Nous avons emis l'hypothese que les CB1Rs peripheriques pourraient initier un circuit nerveux intestin-cerveau-foie par induction de la NGI. Materiels et methodes Des souris vigiles controles et invalidees pour le gene de la G6Pc dans l'intestin (I-G6Pc-/-) sont perfusees en veine porte avec un antagoniste des CB1Rs analogue au Rimonabant (AM251). Leur prise alimentaire est etudiee. Leur neoglucogenese intestinale et hepatique est quantifiee. Un marquage c-fos des noyaux hypothalamiques et des relais centraux des voies spinales et vagales a ete egalement realise. Resultats L'activite de la glucose-6 phosphatase (G6Pase) intestinale est augmentee par l'AM251 (34,8±2,4U/g de proteines vs 19,4±2,8U/g avec le vehicule ; p Discussion Cette etude suggere que l'inhibition des CB1Rs portaux par un antagoniste selectif induirait la NGI et produirait ainsi ses effets benefiques sur la prise alimentaire et l'homeostasie glucidique hepatique. Le systeme nerveux portal serait essentiel dans l'initiation de ce circuit nerveux intestin-cerveaufoie.

Introduction Le passage de glucose dans la veine porte declenche un signal nerveux transmis au cerveau, qui induit l’apparition d’une preference alimentaire, une augmentation de la satiete et un meilleur controle glycemique. Ces derniers effets sont similaires a ceux observes en reponse a un regime hyperproteique, et opposes a ceux d’un regime riche en lipides et en saccharose (diabetogene). Afin d’identifier les supports centraux de ces effets au-dela de l’hypothalamus etudie auparavant, nous avons mesure l’activation d’autres zones cerebrales impliquees dans le controle du metabolisme et de la prise alimentaire. Materiels et Methodes Des rats Sprague-Dawley adultes ont ete soumis pendant 3 jours a un regime hyperglucidique classique (temoin), un regime diabetogene, ou un regime hyperproteique. Un autre groupe d’individus a recu une perfusion portale de glucose a 25umol/kg/min. Sur les cerveaux preleves a ete realisee une detection par immunohistochimie de la proteine c-Fos (marqueur d’activation neuronale), et les cellules marquees ont ete comptees dans chaque zone. Resultats Apres avoir ete relaye dans le noyau parabrachial, le signal issu du glucose portal induit une activation dans l’amygdale (noyau central, +237 % par rapport au temoin), le systeme de recompense (nucleus accumbens, +80 %) et les cortex sensoriels (notamment piriforme, +108 %, et orbitofrontal, +221 %). Ceci traduit l’attribution d’une valeur positive aux perceptions concomitantes a la detection portale de glucose. A l’inverse, les regimes desequilibres diminuent l’activation mesuree dans l’amygdale (-50 a -72 %) et, pour le regime diabetogene, dans les cortex sensoriels (-39 a -84 %), en coherence avec l’habituation des animaux a ces regimes. Dans le bulbe olfactif, le regime hyperproteique et la perfusion portale de glucose induisent une activation similaire des couches mitrales (+211 a +233 %) et granulaires (+126 a +144 %), ce qui reflete l’action d’un agent anorexigene. Conclusion En plus de ses effets metaboliques et de satiete, observes notamment suite a l’ingestion de proteines et probablement inities dans l’hypothalamus, le signal glucose portal induit une activation cortico-limbique coherente avec ses effets connus sur les choix alimentaires.