RESUMEN

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

RESUMEN

BACKGROUND: Breastfeeding (BF) confers metabolic benefits to infants, including reducing risks of metabolic syndrome such as obesity and diabetes later in life. However, the underlying mechanism is not yet fully understood. Hence, we aim to investigate the impacts of BF on the metabolic organs of infants. METHODS: Previous literatures directly studying the influences of BF on offspring's metabolic organs in both animal models and humans were comprehensively reviewed. A microarray dataset of intestinal gene expression comparing infants fed on breastmilk versus formula milk was analyzed. RESULTS: Reanalysis of microarray data showed that BF is associated with enhanced intestinal gluconeogenesis in infants. This resembles observations in other mammalian species showing that BF was also linked to increased gluconeogenesis. CONCLUSIONS: BF is associated with enhanced intestinal gluconeogenesis in infants, which may underpin its metabolic advantages through finetuning metabolic homeostasis. This observation seems to be conserved across species, hinting its biological significance.

Asunto(s)

Lactancia Materna , Síndrome Metabólico , Lactante , Femenino , Animales , Humanos , Gluconeogénesis , Mamíferos

RESUMEN

Maternal overnutrition can dramatically increase the susceptibility of offspring to metabolic diseases, whereas maternal exercise may improve glucose metabolism in offspring. However, the underlying mechanism programming the intergenerational effects of maternal exercise on the benefits of glucose metabolism has not been fully elaborated. C57BL/6 female mice were randomly assigned to four subgroups according to a diet and exercise paradigm before and during pregnancy as follows: NC (fed with normal chow diet and sedentary), NCEx (fed with normal chow diet and running), HF (fed with high-fat diet and sedentary), and HFEx (fed with high-fat diet and running). Integrative 16S rDNA sequencing and mass spectrometry-based metabolite profiling were synchronously performed to characterize the effects of maternal exercise on the gut microbiota composition and metabolite alterations in offspring. Maternal exercise, acting as a natural pharmaceutical intervention, prevented deleterious effects on glucose metabolism in offspring. 16S rDNA sequencing revealed remarkable changes in the gut microbiota composition in offspring. Metabolic profiling indicated multiple altered metabolites, which were enriched in butanoate metabolism signaling in offspring. We further found that maternal exercise could mediate gene expression related to intestinal gluconeogenesis in offspring. In conclusion, our study indicated that maternal running significantly improved glucose metabolism in offspring and counteracted the detrimental effects of maternal high-fat feeding before and during pregnancy. We further demonstrated that maternal voluntary wheel running could integratively program the gut microbiota composition and fecal metabolite changes and then regulate butanoate metabolism and mediate intestinal gluconeogenesis in offspring.

Asunto(s)

Microbioma Gastrointestinal , Ratones , Embarazo , Animales , Femenino , Actividad Motora , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Homeostasis

RESUMEN

While the prevalence of obesity progresses worldwide, the consumption of sugars and dietary fiber increases and decreases, respectively. In this context, NUTRIOSE® soluble fiber is a plant-based food ingredient with beneficial effects in Humans. Here, we studied in mice the mechanisms involved, particularly the involvement of intestinal gluconeogenesis (IGN), the essential function in the beneficial effects of dietary fibers. To determine whether NUTRIOSE® exerts its beneficial effects via the activation of IGN, we studied the effects of dietary NUTRIOSE® on the development of obesity, diabetes and non-alcoholic fatty liver disease (NAFLD), which IGN is able to prevent. To assert the role of IGN in the observed effects, we studied wild-type (WT) and IGN-deficient mice. In line with our hypothesis, NUTRIOSE® exerts metabolic benefits in WT mice, but not in IGN-deficient mice. Indeed, WT mice are protected from body weight gain and NAFLD induced by a high calorie diet. In addition, our data suggests that NUTRIOSE® may improve energy balance by activating a browning process in subcutaneous white adipose tissue. While the gut microbiota composition changes with NUTRIOSE®, this is not sufficient in itself to account for the benefits observed. On the contrary, IGN is obligatory in the NUTRIOSE® benefits, since no benefit take place in absence of IGN. In conclusion, IGN plays a crucial and essential role in the set-up of the beneficial effects of NUTRIOSE®, highlighting the interest of the supplementation of food with healthy ingredients in the context of the current obesity epidemic.

Asunto(s)

Enfermedad del Hígado Graso no Alcohólico , Prebióticos , Humanos , Ratones , Animales , Gluconeogénesis , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Dieta , Metabolismo Energético , Fibras de la Dieta/metabolismo , Obesidad/prevención & control , Obesidad/metabolismo

RESUMEN

BACKGROUND: Untreated celiac disease (CD) patients have increased levels of blood glutamine and a lower duodenal expression of glutaminase (GLS). Intestinal gluconeogenesis (IGN) is a process through which glutamine is turned into glucose in the small intestine, for which GLS is crucial. Animal studies suggest impaired IGN may have long-term effects on metabolic control and be associated with the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The aim of this study was to thoroughly investigate IGN at the gene expression level in children with untreated celiac disease. METHODS: Quantitative polymerase chain reaction (qPCR) was used to quantify the expression of 11 target genes related to IGN using the delta-delta Ct method with three reference genes (GUSB, IPO8, and YWHAZ) in duodenal biopsies collected from 84 children with untreated celiac disease and 58 disease controls. RESULTS: Significantly lower expression of nine target genes involved in IGN was seen in duodenal biopsies from CD patients compared with controls: FBP1, G6PC, GLS, GPT1, PCK1, PPARGC1A, SLC2A2, SLC5A1, and SLC6A19. No significant difference in the expression was observed for G6PC3 or GOT1. CONCLUSIONS: Children with untreated celiac disease have lower expression of genes important for IGN. Further studies are warranted to disentangle whether this is a consequence of intestinal inflammation or due to an impaired metabolic pathway shared with other chronic metabolic diseases. Impaired IGN could be a mechanism behind the increased risk of NAFLD seen in CD patients.

Asunto(s)

Enfermedad Celíaca , Diabetes Mellitus Tipo 2 , Enfermedad del Hígado Graso no Alcohólico , Animales , Enfermedad Celíaca/genética , Gluconeogénesis/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Glutamina/metabolismo , Diabetes Mellitus Tipo 2/patología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología

RESUMEN

Intestinal gluconeogenesis (IGN) is a regulatory function of energy homeostasis. IGN-produced glucose is sensed by the gastrointestinal nervous system and sends a signal to regions of the brain regulating food intake and glucose control. IGN is activated by dietary protein and dietary fibre, and by gastric bypass surgery of obesity. Glutamine, propionate and succinate are the main substrates used for glucose production by IGN. Activation of IGN accounts for the well-known satiety effect of protein-enriched diets and the anti-obesity and anti-diabetes effects associated with fibre feeding and gastric bypass surgery. Genetic activation of IGN in mice shows the same beneficial effects, independently of any nutritional manipulation, including a marked prevention of hepatic steatosis under hypercaloric feeding. The activation of IGN could thus be the basis for new approaches to prevent or correct metabolic diseases in humans.

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Title: La néoglucogenèse intestinale : une fonction insulinomimétique. Abstract: La néoglucogenèse intestinale (NGI) est une fonction régulatrice de l'homéostasie énergétique. Le glucose qu'elle produit est détecté par le système nerveux gastrointestinal et envoie un signal aux régions du cerveau régulant la prise alimentaire et le contrôle glycémique. L'activation de la NGI par les protéines et les fibres alimentaires et par la chirurgie de type by-pass gastrique permet d'expliquer les effets anti-obésité et anti-diabète des régimes enrichis en protéines et/ou en fibres et de la chirurgie bariatrique. L'activation génétique de la NGI chez la souris présente les mêmes effets bénéfiques, indépendamment de toute manipulation nutritionnelle. L'activation de la NGI pourrait ainsi être la base de nouvelles approches préventives ou correctives des maladies métaboliques chez l'homme.

Asunto(s)

Gluconeogénesis , Resistencia a la Insulina , Animales , Fibras de la Dieta/metabolismo , Gluconeogénesis/fisiología , Glucosa/metabolismo , Homeostasis , Humanos , Insulina/metabolismo , Mucosa Intestinal/metabolismo , Ratones , Obesidad/metabolismo

RESUMEN

The gut microbiota plays a crucial role in host health, providing energy and vitamins from food undigested by the gut enzymes of the host. Bacterial metabolites, such as short-chain fatty acids (SCFAs), are essentially metabolized by the gut mucosa. The importance to metabolic health of gut microbiota composition versus function is discussed.

Asunto(s)

Microbioma Gastrointestinal , Reactores Biológicos , Ácidos Grasos Volátiles/metabolismo , Humanos

RESUMEN

High-fat diet (HFD) contributes to metabolic inflammation and glucose metabolism disorder, thereby resulting in the pathogenesis of metabolic syndrome. Accumulating evidence has revealed that some probiotics could improve HFD-induced metabolic inflammation and glucose metabolism disorder. Our previous study has discovered that Lactobacillus acidophilus NX2-6 exhibited in vitro lipid-lowering, antioxidative, and anti-inflammatory activities. This study mainly investigated whether L. acidophilus NX2-6 improved HFD-induced glucose metabolism disorder. The results exhibited that L. acidophilus NX2-6 effectively reduced blood glucose levels and improved glucose tolerance by activating the insulin signaling pathway, promoting glucose uptake, glycolysis, and intestinal gluconeogenesis and suppressing hepatic gluconeogenesis, independent of regulation of glycogen synthesis in the liver and muscle. Enhanced insulin sensitivity was associated with L. acidophilus NX2-6-mediated suppression of inflammatory cascades in the target organs. Meanwhile, L. acidophilus NX2-6 also improved hepatic energy metabolism via the FGF21/AMPKα/PGC-1α/NRF1 pathway. However, L. acidophilus NX2-6 did not affect apoptosis, pyroptosis, inflammation, and endoplasmic reticulum stress in the pancreas of HFD-fed mice. In conclusion, our results indicated that L. acidophilus NX2-6 improved glucose metabolism disorder through enhancing insulin sensitivity, suppressing metabolic inflammation, and promoting energy expenditure.

Asunto(s)

Trastornos del Metabolismo de la Glucosa , Resistencia a la Insulina , Probióticos , Animales , Dieta Alta en Grasa/efectos adversos , Glucosa/metabolismo , Trastornos del Metabolismo de la Glucosa/metabolismo , Secreción de Insulina , Lactobacillus acidophilus , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL

RESUMEN

Dietary fructose overshadows glucose in promoting metabolic complications. Intestinal fructose metabolism (IFM) protects against these effects in rodents, by favoring gluconeogenesis, but the extent of IFM in humans is not known. We therefore aimed to infer the extent of IFM by comparing the contribution of dietary fructose to systemic glucose and hepatic glycogen appearance postprandially. Twelve fasting healthy subjects ingested two protein meals in random order, one supplemented with 50 g 5/95 fructose/glucose (LF) and the other with 50 g 55/45 fructose/glucose (HF). Sources of postprandial plasma glucose appearance and hepatic glycogen synthesis were determined with deuterated water. Plasma glucose excursions, as well as pre- and post-meal insulin, c-peptide, and triglyceride levels were nearly identical for both meals. The total gluconeogenic contribution to plasma glucose appearance was significantly higher for HF versus LF (65 ± 2% vs. 34 ± 3%, p < 0.001). For HF, Krebs cycle anaplerosis accounted for two-thirds of total gluconeogenesis (43 ± 2%) with one-third from Triose-P sources (22 ± 1%). With LF, three-quarters of the total gluconeogenic contribution originated via Krebs cycle anaplerosis (26 ± 2%) with one-quarter from Triose-P sources (9 ± 2%). HF and LF gave similar direct and indirect pathway contributions to hepatic glycogen synthesis. Increasing the fructose/glucose ratio had significant effects on glucose appearance sources but no effects on hepatic glycogen synthesis sources, consistent with extensive IFM. The majority of fructose carbons were converted to glucose via the Krebs cycle.

RESUMEN

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.

Asunto(s)

Ansiedad/metabolismo , Conducta Animal/fisiología , Depresión/metabolismo , Fibras de la Dieta/metabolismo , Proteínas en la Dieta/metabolismo , Gluconeogénesis/fisiología , Intestino Delgado/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones

RESUMEN

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.

Asunto(s)

Gluconeogénesis , Intestinos , Animales , Glucosa , Ratones , Obesidad/prevención & control , Saciedad

RESUMEN

Fructose consumption by rodents modulates both hepatic and intestinal lipid metabolism and gluconeogenesis. We have previously demonstrated that in utero exposure to dexamethasone (DEX) interacts with fructose consumption during adult life to exacerbate hepatic steatosis in rats. The aim of this study was to clarify if adult rats born to DEX-treated mothers would display differences in intestinal gluconeogenesis after excessive fructose intake. To address this issue, female Wistar rats were treated with DEX during pregnancy and control (CTL) mothers were kept untreated. Adult offspring born to CTL and DEX-treated mothers were assigned to receive either tap water (Control-Standard Chow (CTL-SC) and Dexamethasone-Standard Chow (DEX-SC)) or 10% fructose in the drinking water (CTL-fructose and DEX-fructose). Fructose consumption lasted for 80 days. All rats were subjected to a 40 h fasting before sample collection. We found that DEX-fructose rats have increased glucose and reduced lactate in the portal blood. Jejunum samples of DEX-fructose rats have enhanced phosphoenolpyruvate carboxykinase (PEPCK) expression and activity, higher facilitated glucose transporter member 2 (GLUT2) and facilitated glucose transporter member 5 (GLUT5) content, and increased villous height, crypt depth, and proliferating cell nuclear antigen (PCNA) staining. The current data reveal that rats born to DEX-treated mothers that consume fructose during adult life have increased intestinal gluconeogenesis while recapitulating metabolic and morphological features of the neonatal jejunum phenotype.

Asunto(s)

Dexametasona/efectos adversos , Carbohidratos de la Dieta/efectos adversos , Células Epiteliales/patología , Fructosa/efectos adversos , Gluconeogénesis , Mucosa Intestinal/citología , Mucosa Intestinal/metabolismo , Yeyuno/metabolismo , Exposición Materna/efectos adversos , Intercambio Materno-Fetal/fisiología , Efectos Tardíos de la Exposición Prenatal , Fenómenos Fisiológicos Nutricionales de los Animales/fisiología , Animales , Femenino , Transportador de Glucosa de Tipo 2/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Metabolismo de los Lípidos , Fenómenos Fisiologicos Nutricionales Maternos/fisiología , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , Embarazo , Ratas Wistar

RESUMEN

OBJECTIVES: Metabolic surgery has been proven to be widely effective for the control of glucose and weight in patients with type 2 diabetes and obesity. However, the effects of bariatric surgery on nonobesity type 2 diabetes and its metabolism are still unclear. This study aimed to measure the effects of duodenal-jejunal exclusion on glycometabolism in nonobese rats with type 2 diabetes and to investigate its mechanisms. METHODS: Goto-Kakizaki rats and Sprague-Dawley rats were divided into duodenal-jejunal exclusion operation groups and sham operation groups, respectively. The glucose-relative parameters were measured before and after operation. Eight weeks postoperation, the levels of the key regulators of intestinal gluconeogenesis and the crucial proteins of hepatic insulin signalling were evaluated. RESULTS: Postoperatively, the concentrations of blood glucose declined, and the insulin sensitivity increased significantly in rats with diabetes. However, there was no obvious reduction in weight. Eight weeks postoperatively, the mRNA levels of glucose-6-phosphatase and phosphoenolpyruvate pyruvate kinase in the jejunum and the levels of insulin receptor substrate-2 and glucose transporter-2 in the liver were significantly increased compared with the rats that had undergone the sham operation. CONCLUSIONS: Duodenal-jejunal exclusion surgery is an effective procedure for improving glucose metabolism independent of weight loss in nonobese rats with diabetes. The molecular mechanisms might be associated with a series of processes, including intestinal gluconeogenesis and the hepatic insulin signaling pathway.

Asunto(s)

Cirugía Bariátrica , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/cirugía , Duodeno/cirugía , Gluconeogénesis/genética , Yeyuno/cirugía , Hígado/metabolismo , Estómago/cirugía , Anastomosis Quirúrgica , Animales , Peso Corporal , Diabetes Mellitus Tipo 2/metabolismo , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 2/genética , Transportador de Glucosa de Tipo 2/metabolismo , Glucosa-6-Fosfatasa/genética , Glucosa-6-Fosfatasa/metabolismo , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Resistencia a la Insulina , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Yeyuno/metabolismo , Fosfoenolpiruvato Carboxiquinasa (GTP)/genética , Fosfoenolpiruvato Carboxiquinasa (GTP)/metabolismo , ARN Mensajero/metabolismo , Ratas

RESUMEN

OBJECTIVE: Hepatic 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. DESIGN: To 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. RESULTS: We 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. CONCLUSION: We conclude that IGN per se has the capacity of preventing hepatic steatosis and its eventual evolution toward NAFLD.

Asunto(s)

Tracto Gastrointestinal/metabolismo , Gluconeogénesis/fisiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Obesidad/fisiopatología , Animales , Quimiocina CCL2/metabolismo , Dieta Alta en Grasa , Interleucina-6/metabolismo , Hígado/inervación , Hígado/metabolismo , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Tirosina 3-Monooxigenasa/metabolismo

RESUMEN

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.

Asunto(s)

Derivación Gástrica , Obesidad/metabolismo , Obesidad/cirugía , Animales , Peso Corporal , Masculino , Ratones , Ratones Endogámicos C57BL , Pérdida de Peso

RESUMEN

Type 2 diabetes prevalence is increasing dramatically worldwide. Metabolic surgery is the most effective treatment for selected patients with diabetes and/or obesity. When compared to intensive medical therapy and lifestyle intervention, metabolic surgery has shown superiority in achieving glycemic improvement, reducing number of medications and cardiovascular risk factors, which translates in long-term benefits on cardiovascular morbidity and mortality. The mechanisms underlying diabetes improvement after metabolic surgery have not yet been clearly understood but englobe a complex interaction among improvements in beta cell function and insulin secretion, insulin sensitivity, intestinal gluconeogenesis, changes in glucose utilization, and absorption by the gut and changes in the secretory pattern and morphology of adipose tissue. These are achieved through different mediators which include an enhancement in gut hormones release, especially, glucagon-like peptide 1, changes in bile acids circulation, gut microbiome, and glucose transporters expression. Therefore, this review aims to provide a comprehensive appraisal of what is known so far to better understand the mechanisms through which metabolic surgery improves glycemic control facilitating future research in the field.

RESUMEN

In the context of the obesity epidemic, dietary fibers that are found essentially in fruit and vegetables attract more and more attention, since they exert numerous metabolic benefits resulting in the moderation of body weight. Short-chain fatty acids, such as propionate and butyrate, produced through their fermentation by the intestinal microbiota, have long been thought to be the mediators of these benefits. In fact, propionate and butyrate were recently shown to activate intestinal gluconeogenesis, a function exerting metabolic benefits via its capacity of signaling to the brain by gastrointestinal nerves. Recently, succinate, the precursor of propionate in the bacterial metabolism, has also been shown to exert signaling properties, including the activation of intestinal gluconeogenesis.

Asunto(s)

Encéfalo/fisiología , Metabolismo Energético/fisiología , Microbioma Gastrointestinal/fisiología , Intestinos/inervación , Intestinos/fisiología , Ácido Succínico/metabolismo , Animales , Homeostasis , Humanos , Red Nerviosa/fisiología , Transducción de Señal/fisiología

RESUMEN

A large number of genomic studies have reported associations between the gut microbiota composition and metabolic diseases such as obesity or type 2 diabetes. This led to the widespread idea that a causal relationship could exist between intestinal microbiota and metabolic diseases. At odds with this idea, some compelling studies reported that global changes in microbiota composition have no effect on the host metabolism in obese mice or humans. However, specific bacteria are able to confer host metabolic benefits, such as Akkermansia muciniphila or Prevotella copri, when they are given by gavage in obese mice. A crucial link by which gut bacteria communicate with the host mucosa is based on metabolites or low-molecular-weight compounds. Among them, short-chain fatty acids produced from the fermentation of dietary fibers initiate beneficial effects on the host metabolism via the activation of intestinal gluconeogenesis (a mucosal function exerting antidiabetic and antiobesity effects through the activation of gut-brain neural circuits). However, fermentation of short-chain fatty acids is a function that is widespread among the main bacterial phyla and thus weakly depends on microbiota composition. Therefore, even if some bacteria may confer on the host metabolic benefits, the causal role of microbiota in metabolic diseases is not established.

Asunto(s)

Microbioma Gastrointestinal , Enfermedades Metabólicas , Animales , Humanos

RESUMEN

Animal studies indicate that the composition of gut microbiota may be involved in the progression of insulin resistance to type 2 diabetes. Probiotics and/or prebiotics could be a promising approach to improve insulin sensitivity by favourably modifying the composition of the gut microbial community, reducing intestinal endotoxin concentrations and decreasing energy harvest. The aim of the present review was to investigate the effects of probiotics, prebiotics and synbiotics (a combination of probiotics and prebiotics) on insulin resistance in human clinical trials and to discuss the potential mechanisms whereby probiotics and prebiotics improve glucose metabolism. The anti-diabetic effects of probiotics include reducing pro-inflammatory cytokines via a NF-κB pathway, reduced intestinal permeability, and lowered oxidative stress. SCFA play a key role in glucose homeostasis through multiple potential mechanisms of action. Activation of G-protein-coupled receptors on L-cells by SCFA promotes the release of glucagon-like peptide-1 and peptide YY resulting in increased insulin and decreased glucagon secretion, and suppressed appetite. SCFA can decrease intestinal permeability and decrease circulating endotoxins, lowering inflammation and oxidative stress. SCFA may also have anti-lipolytic activities in adipocytes and improve insulin sensitivity via GLUT4 through the up-regulation of 5'-AMP-activated protein kinase signalling in muscle and liver tissues. Resistant starch and synbiotics appear to have favourable anti-diabetic effects. However, there are few human interventions. Further well-designed human clinical studies are required to develop recommendations for the prevention of type 2 diabetes with pro- and prebiotics.

Asunto(s)

Microbioma Gastrointestinal , Resistencia a la Insulina , Insulina/metabolismo , Intestinos/microbiología , Prebióticos , Probióticos , Simbióticos , Animales , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiología , Diabetes Mellitus Tipo 2/prevención & control , Ácidos Grasos Volátiles/metabolismo , Humanos , Hipoglucemiantes/uso terapéutico , Inflamación/metabolismo , Inflamación/microbiología , Inflamación/prevención & control , FN-kappa B/metabolismo , Estrés Oxidativo

RESUMEN

In this study we addressed the questions whether an Atlantic brown algae extract (BAE) affects diet induced obesity in mice and which would be the primary targets and underlying key mechanisms. Male C57 BL/6 mice were fed a hypercaloric diet, referred to as high fat diet (HFD), supplemented with a freeze-dried aqueous BAE from Saccorhiza polyschides (5 %) for 8 months. Compared to the control group, dietary BAE supplementation significantly attenuated increase in body weight and fat mass. We observed apparent metabolic improvement including normalization of blood glucose, reduced plasma leptin, reduced fecal bile salt hydrolase activity with lower microbial production of toxic bile acid metabolites in the gut and increased systemic bile acid circulation in BAE-fed mice counteracting adverse effects of long term HFD feeding. Survival of mice receiving dietary BAE supplementation appeared slightly enhanced; however, median and maximal life spans as well as hepatic mTOR activation were not significantly different between BAE and control mice. We suggest that the beneficial metabolic effects of our BAE are at least partly mediated by alterations in gut microbiota associated with fermentation of indigestible polysaccharides that are major components of brown algae such as alginates and fucoidans. We moreover propose a multi-factorial mechanism that involves profound alterations in bile acid homeostasis, changes in intestinal and systemic glucose metabolism likely including increased intestinal gluconeogenesis, increased activity of the intestinally derived hormone GLP-1 contributing to promote systemic insulin sensitivity, and inhibition of α-amylase activity, which expectably limits dietary carbohydrate digestion and glucose release.