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Intestinal gluconeogenesis (IGN) regulates adult energy homeostasis in part by controlling the same hypothalamic targets as leptin. In neonates, leptin exhibits a neonatal surge controlling axonal outgrowth between the different hypothalamic nuclei involved in feeding circuits and autonomic innervation of peripheral tissues involved in energy and glucose homeostasis. Interestingly, IGN is induced during this specific time-window. We hypothesized that the neonatal pic of IGN also regulates the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues. We genetically induced neonatal IGN by overexpressing G6pc1 the catalytic subunit of glucose-6-phosphatase (the mandatory enzyme of IGN) at birth or at twelve days after birth. The neonatal development of hypothalamic feeding circuits was studied by measuring Agouti-related protein (AgRP) and Pro-opiomelanocortin (POMC) fiber density in hypothalamic nuclei of 20-day-old pups. The effect of the neonatal induction of intestinal G6pc1 on sympathetic innervation of the adipose tissues was studied via tyrosine hydroxylase (TH) quantification. The metabolic consequences of the neonatal induction of intestinal G6pc1 were studied in adult mice challenged with a high-fat/high-sucrose (HFHS) diet for 2 months. Induction of intestinal G6pc1 at birth caused a neonatal reorganization of AgRP and POMC fiber density in the paraventricular nucleus of the hypothalamus, increased brown adipose tissue tyrosine hydroxylase levels, and protected against high-fat feeding-induced metabolic disorders. In contrast, inducing intestinal G6pc1 12 days after birth did not impact AgRP/POMC fiber densities, adipose tissue innervation or adult metabolism. These findings reveal that IGN at birth but not later during postnatal life controls the development of hypothalamic feeding circuits and sympathetic innervation of adipose tissues, promoting a better management of metabolism in adulthood. • Intestinal gluconeogenesis exhibits a perinatal surge, peaking 5 days after birth. • Perinatal intestinal gluconeogenesis controls hypothalamic melanocortin circuitry. • Perinatal intestinal gluconeogenesis participates in adult metabolism programming. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • 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. [ABSTRACT FROM AUTHOR]

Abstract Objective Ectopic lipid accumulation in the liver and kidneys is a hallmark of metabolic diseases leading to non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). Moreover, recent data have highlighted a strong correlation between NAFLD and CKD incidences. In this study, we use two mouse models of hepatic steatosis or CKD, each initiated independently of the other upon the suppression of glucose production specifically in the liver or kidneys, to elucidate the mechanisms underlying the development of CKD in the context of NAFLD-like pathology. Methods Mice with a deletion of G6pc , encoding glucose-6 phosphatase catalytic subunit, specifically in the liver (L.G6pc−/− mice) or the kidneys (K.G6pc−/− mice), were fed with either a standard diet or a high fat/high sucrose (HF/HS) diet during 9 months. These mice represent two original models of a rare metabolic disease named Glycogen Storage Disease Type Ia (GSDIa) that is characterized by both NAFLD-like pathology and CKD. Two other groups of L.G6pc−/− and K.G6pc−/− mice were fed a standard diet for 6 months and then treated with fenofibrate for 3 months. Lipid and glucose metabolisms were characterized, and NAFLD-like and CKD damages were evaluated. Results Lipid depot exacerbation upon high-calorie diet strongly accelerated hepatic and renal pathologies induced by the G6pc -deficiency. In L.G6pc−/− mice, HF/HS diet increased liver injuries, characterized by higher levels of plasmatic transaminases and increased hepatic tumor incidence. In K.G6pc−/− mice, HF/HS diet increased urinary albumin and lipocalin 2 excretion and aggravated renal fibrosis. In both cases, the worsening of NAFLD-like injuries and CKD was independent of glycogen content. Furthermore, fenofibrate, via the activation of lipid oxidation significantly decreased the hepatic or renal lipid accumulations and prevented liver or kidney damages in L.G6pc−/− and K.G6pc−/− mice, respectively. Finally, we show that L.G6pc−/− mice and K.G6pc−/− mice developed NAFLD-like pathology and CKD independently. Conclusions This study highlights the crucial role that lipids play in the independent development of both NAFLD and CKD and demonstrates the importance of lipid-lowering treatments in various metabolic diseases featured by lipid load, from the "rare" GSDIa to the "epidemic" morbid obesity or type 2 diabetes. Graphical abstract Image 1 Highlights • Exacerbating lipid accumulation aggravates liver/kidney injury in GSDI. • Fenofibrate-mediated PPARα activation induces hepatic and renal lipid turnover. • Increased lipid turnover prevents glycogen synthesis and accumulation. • PPARα–mediated metabolic reprograming prevents hepatic and renal GSDI complications. • NAFLD and CKD develop independently. [ABSTRACT FROM AUTHOR]

Abstract Objective The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut–brain–liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation. Methods We studied mice whose glucose-6-phosphatase (G6Pase) catalytic subunit (G6PC) is specifically knocked down in the kidneys (K-G6pc-/- mice) during fasting. We also examined the additional effects of intestinal G6pc deletion, renal denervation and vitamin D administration on the altered glucose metabolism in K-G6pc-/- mice. Results Compared with WT mice, K-G6pc-/- mice exhibited (1) lower glycemia, (2) enhanced intestinal but not hepatic G6Pase activity, (3) enhanced hepatic glucokinase (GK encoded by Gck) activity, (4) increased hepatic glucose-6-phosphate and (5) hepatic glycogen spared from exhaustion during fasting. Increased hepatic Gck expression in the post-absorptive state could be dependent on the enhancement of insulin signal (AKT phosphorylation) in K-G6pc-/- mice. In contrast, the increase in hepatic GK activity was not observed in mice with both kidney- and intestine-knockout (KI-G6pc-/- mice). Hepatic Gck gene expression and hepatic AKT phosphorylation were reduced in KI-G6pc-/- mice. Renal denervation by capsaicin did not induce any effect on glucose metabolism in K-G6pc-/- mice. Plasma level of 1,25 (OH) 2 D 3 , an active form of vitamin D, was decreased in K-G6pc-/- mice. Interestingly, the administration of 1,25 (OH) 2 D 3 prevented the enhancement of intestinal gluconeogenesis and hepatic GK activity and blocked the accumulation of hepatic glycogen otherwise observed in K-G6pc-/- mice during fasting. Conclusions A diminution in renal gluconeogenesis that is accompanied by a decrease in blood vitamin D promotes a novel repartition of EGP among glucose producing organs during fasting, featured by increased intestinal gluconeogenesis that leads to sparing glycogen stores in the liver. Our data suggest a possible involvement of a crosstalk between the kidneys and intestine (via the vitamin D system) and the intestine and liver (via a neural gut-brain axis), which might take place in the situations of deficient renal glucose production, such as chronic kidney disease. Highlights • Reduced renal G6Pase activity promotes increased hepatic glycogen during fasting. • Reduced renal G6Pase activity enhances intestinal but not hepatic G6Pase activity. • Reduced renal G6Pase activity results in low vitamin D level. • Vitamin D injection restores metabolism in mice with reduced renal G6Pase activity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Deregulation of hepatic glucose production is a key driver in the pathogenesis of diabetes, but its short-term regulation is incompletely deciphered. According to textbooks, glucose is produced in the endoplasmic reticulum by glucose-6-phosphatase (G6Pase) and then exported in the blood by the glucose transporter GLUT2. However, in the absence of GLUT2, glucose can be produced by a cholesterol-dependent vesicular pathway, which remains to be deciphered. Interestingly, a similar mechanism relying on vesicle trafficking controls short-term G6Pase activity. We thus investigated whether Caveolin-1 (Cav1), a master regulator of cholesterol trafficking, might be the mechanistic link between glucose production by G6Pase in the ER and glucose export through a vesicular pathway. Glucose production from fasted mice lacking Cav1, GLUT2 or both proteins was measured in vitro in primary culture of hepatocytes and in vivo by pyruvate tolerance tests. The cellular localization of Cav1 and the catalytic unit of glucose-6-phosphatase (G6PC1) were studied by western blotting from purified membranes, immunofluorescence on primary hepatocytes and fixed liver sections and by in vivo imaging of chimeric constructs overexpressed in cell lines. G6PC1 trafficking to the plasma membrane was inhibited by a broad inhibitor of vesicular pathways or by an anchoring system retaining G6PC1 specifically to the ER membrane. Hepatocyte glucose production is reduced at the step catalyzed by G6Pase in the absence of Cav1. In the absence of both GLUT2 and Cav1, gluconeogenesis is nearly abolished, indicating that these pathways can be considered as the two major pathways of de novo glucose production. Mechanistically, Cav1 colocalizes but does not interact with G6PC1 and controls its localization in the Golgi complex and at the plasma membrane. The localization of G6PC1 at the plasma membrane is correlated to glucose production. Accordingly, retaining G6PC1 in the ER reduces glucose production by hepatic cells. Our data evidence a pathway of glucose production that relies on Cav1-dependent trafficking of G6PC1 to the plasma membrane. This reveals a new cellular regulation of G6Pase activity that contributes to hepatic glucose production and glucose homeostasis. [Display omitted] • Hepatic gluconeogenesis depends on GLUT2 and Cav1-dependent pathways. • Cav1 controls the localization of glucose-6-phosphatase in fasted hepatocytes. • Glucose-6-phosphatase moves from the endoplasmic reticulum to the plasma membrane. • Glucose-6-phosphatase couples glucose production and release at the plasma membrane. [ABSTRACT FROM AUTHOR]

Summary 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. [ABSTRACT FROM AUTHOR]

Objective Insulin-like peptide 5 (INSL5) is a recently identified gut hormone that is produced predominantly by L-cells in the colon, but its function is unclear. We have previously shown that colonic expression of the gene for the L-cell hormone GLP-1 is high in mice that lack a microbiota and thus have energy-deprived colonocytes. Our aim was to investigate if energy deficiency also affected colonic Insl5 expression and to identify a potential role of INSL5. Methods We analyzed colonic Insl5 expression in germ-free (GF), conventionally raised (CONV-R), conventionalized (CONV-D) and antibiotic-treated mice, and also assessed the effect of dietary changes on colonic Insl5 expression. In addition, we characterized the metabolic phenotype of Insl5 −/− mice. Results We showed that colonic Insl5 expression was higher in GF and antibiotic-treated mice than in CONV-R mice, whereas Insl5 expression in the brain was higher in CONV-R versus GF mice. We also observed that colonic Insl5 expression was suppressed by increasing the energy supply in GF mice by colonization or high-fat feeding. We did not observe any differences in food intake, gut transit or oral glucose tolerance between Insl5 −/− and wild-type mice. However, we showed impaired intraperitoneal glucose tolerance in Insl5 −/− mice. We also observed improved insulin tolerance and reduced hepatic glucose production in Insl5 −/− mice. Conclusions We have shown that colonic Insl5 expression is regulated by the gut microbiota and energy availability. We propose that INSL5 is a hormone that could play a role in promoting hepatic glucose production during periods of energy deprivation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the role of bile routing modification on the beneficial effects of gastric bypass surgery on glucose and energy metabolism. Background: Gastric bypass surgery (GBP) promotes early improvements in glucose and energy homeostasis in obese diabetic patients. A suggested mechanism associates a decrease in hepatic glucose production to an enhanced intestinal gluconeogenesis. 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 midjejunum or the mid-ileum to match the modified bile delivery in the gut occurring in GBP. Body weight, food intake, glucose tolerance, insulin sensitivity, and food preference were analyzed. The expression 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 marked improvement in glucose control. Bile bioavailability modification is causal because a bile acid sequestrant suppresses the beneficial effects of bile diversions on glucose control. In agreement with the inhibitory role of bile acids on gluconeogenesis, bile diversions promote a blunting in hepatic glucose production, whereas intestinal gluconeogenesis is increased in the gut segments devoid of bile. In rats fed a high-fat-highsucrose diet, bile diversions improve glucose control and dramatically decrease food intake because of an acquired disinterest in fatty food. Conclusions: This study shows that bile routing modification is a key mechanistic feature in the beneficial outcomes of GBP. [ABSTRACT FROM AUTHOR]

Objectives Certain nutrients positively regulate energy homeostasis via intestinal gluconeogenesis (IGN). The objective of this study was to evaluate the impact of a deficient IGN in glucose control independently of nutritional environment. Methods We used mice deficient in the intestine glucose-6 phosphatase catalytic unit, the key enzyme of IGN (I- G6pc −/− mice). We evaluated a number of parameters involved in energy homeostasis, including insulin sensitivity (hyperinsulinemic euglycaemic clamp), the pancreatic function (insulin secretion in vivo and in isolated islets) and the hypothalamic homeostatic function (leptin sensitivity). Results Intestinal- G6pc −/− mice exhibit slight fasting hyperglycaemia and hyperinsulinemia, glucose intolerance, insulin resistance and a deteriorated pancreatic function, despite normal diet with no change in body weight. These defects evoking type 2 diabetes (T2D) derive from the basal activation of the sympathetic nervous system (SNS). They are corrected by treatment with an inhibitor of α-2 adrenergic receptors. Deregulation in a key target of IGN, the homeostatic hypothalamic function (highlighted here through leptin resistance) is a mechanistic link. Hence the leptin resistance and metabolic disorders in I- G6pc −/− mice are corrected by rescuing IGN by portal glucose infusion. Finally, I- G6pc −/− mice develop the hyperglycaemia characteristic of T2D more rapidly under high fat/high sucrose diet. Conclusions Intestinal gluconeogenesis is a mandatory function for the healthy neural control of glucose homeostasis. [ABSTRACT FROM AUTHOR]

Hypoglycemia is a clinical hallmark of severe malaria, the often-lethal outcome of Plasmodium falciparum infection. Here, we report that malaria-associated hypoglycemia emerges from a non-canonical resistance mechanism, whereby the infected host reduces glycemia to starve Plasmodium. This hypometabolic response is elicited by labile heme, a byproduct of hemolysis that induces illness-induced anorexia and represses hepatic glucose production. While transient repression of hepatic glucose production prevents unfettered immune-mediated inflammation, organ damage, and anemia, when sustained over time it leads to hypoglycemia, compromising host energy expenditure and adaptive thermoregulation. The latter arrests the development of asexual stages of Plasmodium via a mechanism associated with parasite mitochondrial dysfunction. In response, Plasmodium activates a transcriptional program associated with the reduction of virulence and sexual differentiation toward the generation of transmissible gametocytes. In conclusion, malaria-associated hypoglycemia represents a trade-off of a hypometabolic-based defense strategy that balances parasite virulence versus transmission. [Display omitted] • Repression of hepatic gluconeogenesis by labile heme drives malarial hypoglycemia • Hypoglycemia lowers Plasmodium virulence • Malarial hypoglycemia compromises host energy metabolism and thermoregulation • Plasmodium undergoes gametocytogenesis in response to hypoglycemia Malaria-associated hypoglycemia develops as a trade-off of a non-canonical resistance mechanism against Plasmodium infection based on restricting parasite access to glucose. In response, Plasmodium reduces its virulence in favor of transmission, an evolutionarily conserved host-pathogen cooperative metabolic behavior. [ABSTRACT FROM AUTHOR]

Recent data have emphasized that the gastrointestinal nervous system is preponderant in the sensing of nutrients and hormones and its translation in terms of control of food intake by the central nervous system. More specifically, the gastrointestinal neural system participates in the control of hunger via the sensing of at least two major macronutrients, e.g. glucose and protein, which may control hunger sensations from the portal vein. Protein are first sensed by mu-opioid receptors present in the portal vein walls to induce intestinal gluconeogenesis- via a reflex arc and next portal glucose sensing. The gastrointestinal nervous system may also account for the rapid benefits of gastric bypass surgeries on energy homeostasis (hunger and body weight) and glucose homeostasis (insulin sensitivity). This knowledge provides novel mechanisms of control of body weight, which might be useful to envision future approaches of prevention or treatment of obesity. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Similar to the liver and kidneys, the intestine has been strongly suggested to be a gluconeogenic organ. However, the precise contribution of the intestine to endogenous glucose production (EGP) remains to be determined. To define the quantitative role of intestinal gluconeogenesis during long-term fasting, we compared changes in blood glucose during prolonged fasting in mice with a liver-deletion of the glucose-6 phosphatase catalytic (G6PC) subunit (LKO) and in mice with a combined deletion of G6PC in both the liver and the intestine (ILKO). Materials/Methods: The LKO and ILKO mice were studied after 6h and 40h of fasting by measuring metabolic and hormonal plasmatic parameters, as well as the expression of gluconeogenic enzymes in the liver, kidneys and intestine. Results: After a transient hypoglycemic episode (approximately 60mg/dL) because of their incapacity to mobilize liver glycogen, the LKO mice progressively re-increased their plasma glucose to reach a glycemia comparable to that of wild-type mice (90mg/dL) from 30h of fasting. This increase was associated with a rapid induction of renal and intestinal gluconeogenic gene expression, driven by glucagon, glucocorticoids and acidosis. The ILKO mice exhibited a similar induction of renal gluconeogenesis. However, these mice failed to re-increase their glycemia and maintained a plasma glucose level of only 60mg/dL throughout the 48h-fasting period. Conclusions: These data indicate that intestinal glucose production is essential to maintain glucose homeostasis in the absence of hepatic glucose production during fasting. These data provide a definitive quantitative estimate of the capacity of intestinal gluconeogenesis to sustain EGP during long-term fasting. [Copyright &y& Elsevier]

Abstract: 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. [Copyright &y& Elsevier]

Summary: 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. [Copyright &y& Elsevier]

Summary: Protein feeding is known to decrease hunger and subsequent food intake in animals and humans. It has also been suggested that glucose appearance into portal vein, as occurring during meal assimilation, may induce comparable effects. Here, we connect these previous observations by reporting that intestinal gluconeogenesis (i.e., de novo synthesis of glucose) is induced during the postabsorptive time (following food digestion) in rats specifically fed on protein-enriched diet. This results in glucose release into portal blood, counterbalancing the lowering of glycemia resulting from intestinal glucose utilization. Comparable infusions into the portal vein of control postabsorptive rats (fed on starch-enriched diet) decrease food consumption and activate the hypothalamic nuclei regulating food intake. Similar hypothalamic activation occurs on protein feeding. All these effects are absent after denervation of the portal vein. Thus, portal sensing of intestinal gluconeogenesis may be a novel mechanism connecting the macronutrient composition of diet to food intake. [Copyright &y& Elsevier]

Purpose Of Review: It has become clear during the past few years that the intestine is more than a digestive tract. In addition to its role as a subtle endocrine organ, its participation in endogenous glucose production, a property so far believed to be restricted to the liver and kidney, has been emphasized.Recent Findings: The role of the gut in the regulation of glucose homeostasis has received further experimental accreditation from both animal and human studies. In relation to the molecular mechanisms of control of glucose production the potential regulatory role of glutaminase and glycerokinase has been suggested from studies of fasting, and the transcription of the glucose-6 phosphatase gene has been specified in an intestinal context. Furthermore, two newly described metabolic pathways accounting for the transepithelial transport of glucose have received further support: from the intestinal lumen to inside the enterocyte, involving a translocation of the glucose transporter Glut2 to the apical membrane, and from inside the enterocyte into the blood, involving glucose 6-phosphatase and independent of Glut2.Summary: The new knowledge regarding the control of glucose, glutamine, and glycerol metabolisms in the small intestine should be of interest to those who care for diabetic or septic patients, or are involved in nutrition research in humans. They should also be of importance in the knowledge of inherited genetic deficiencies, such as glycogen storage disease type 1 (Von Gierke disease) and the Fanconi-Bickel and glucose-galactose malabsorption syndromes. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disorder caused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor glycemic control in GSD Ia is associated with hypertriglyceridemia, hepatocellular adenoma and carcinoma, and also with an increased bleeding tendency of unknown origin. To evaluate the effect of glycemic control on leukocyte levels and coagulation in GSD Ia, we employed hepatocyte-specific G6pc1 deficient (L -G6pc −/− ) mice under fed or fasted conditions, to match good or poor glycemic control in GSD Ia, respectively. We found that fasting-induced hypoglycemia in L -G6pc −/− mice decreased blood leukocytes, specifically proinflammatory Ly6Chi monocytes, compared to controls. Refeeding reversed this decrease. The decrease in Ly6Chi monocytes was accompanied by an increase in plasma corticosterone levels and was prevented by the glucocorticoid receptor antagonist mifepristone. Further, fasting-induced hypoglycemia in L -G6pc −/− mice prolonged bleeding time in the tail vein bleeding assay, with reversal by refeeding. This could not be explained by changes in coagulation factors V, VII, or VIII, or von Willebrand factor. While the prothrombin and activated partial thromboplastin time as well as total platelet counts were not affected by fasting-induced hypoglycemia in L -G6pc −/− mice, ADP-induced platelet aggregation was disturbed. These studies reveal a relationship between fasting-induced hypoglycemia, decreased blood monocytes, and disturbed platelet aggregation in L -G6pc −/− mice. While disturbed platelet aggregation likely accounts for the bleeding phenotype in GSD Ia, elevated plasma corticosterone decreases the levels of proinflammatory monocytes. These studies highlight the necessity of maintaining good glycemic control in GSD Ia. • Fasting-induced hypoglycemia in hepatocyte-specific G6pc1 deficiency disturbs platelet aggregation. • Fasting-induced hypoglycemia in hepatocyte-specific G6pc1 deficiency decreases blood monocytes. • Fasting-induced hypoglycemia in hepatocyte-specific G6pc1 deficiency increases plasma corticosterone. [ABSTRACT FROM AUTHOR]

Glucose production in the blood requires the expression of glucose-6 phosphatase (G6Pase), a key enzyme that allows glucose-6 phosphate (G6P) hydrolysis into free glucose and inorganic phosphate. We previously reported that the hepatic suppression of G6Pase leads to G6P accumulation and to metabolic reprogramming in hepatocytes from liver G6Pase-deficient mice (L.G6pc−/−). Interestingly, the activity of the transcription factor carbohydrate response element-binding protein (ChREBP), central for de novo lipid synthesis, is markedly activated in L.G6pc−/− mice, which consequently rapidly develop NAFLD-like pathology. In the current work, we assessed whether a selective deletion of ChREBP could prevent hepatic lipid accumulation and NAFLD initiation in L.G6pc−/− mice. We generated liver-specific ChREBP (L.Chrebp−/−)- and/or G6Pase (L.G6pc−/−)-deficient mice using a Cre-lox strategy in B6.SACreERT2 mice. Mice were fed a standard chow diet or a high-fat diet for 10 days. Markers of hepatic metabolism and cellular stress were analysed in the liver of control, L. G6pc−/−, L. Chrebp−/− and double knockout (i.e., L.G6pc−/−.Chrebp−/−) mice. We observed that there was a dramatic decrease in lipid accumulation in the liver of L.G6pc−/−.Chrebp−/− mice. At the mechanistic level, elevated G6P concentrations caused by lack of G6Pase are rerouted towards glycogen synthesis. Importantly, this exacerbated glycogen accumulation, leading to hepatic water retention and aggravated hepatomegaly. This caused animal distress and hepatocyte damage, characterised by ballooning and moderate fibrosis, paralleled with acute endoplasmic reticulum stress. Our study reveals the crucial role of the ChREBP-G6Pase duo in the regulation of G6P-regulated pathways in the liver. • Hepatic deletion of both ChREBP and glucose-6 phosphatase collapses liver lipids. • Double deletion leads to excessive glycogen storage and a liver swollen with water. • Hepatic deletion of both ChREBP and glucose-6 phosphatase leads to death. • Glucose-6 phosphate homeostasis in hepatocytes is a vital function. [ABSTRACT FROM AUTHOR]