RESUMEN
Mounting evidence showed that excess selenium (10.0-15.0-fold of adequate Se) intake caused severe hepatic lipid deposition in the vertebrate. However, the underlying mechanism remains unclear. The study was performed to elucidate the mechanism of Se supranutrition mediated-changes of lipid deposition and metabolism. We found that dietary excessive Se addition increased hepatic TGs and glucose contents, up-regulated lipogenic enzyme activities and reduced hepatic glycogen contents. Transcriptomic and immunoblotting analysis showed that Se supranutrition significantly influenced serine/threonine kinase 1 (AKT1)-forkhead box O3a (FOXO3a)-PYGL signaling and protein levels of SELENOF. Knockdown of SELENOF and PYGL by RNA interference revealed that the AKT1-FOXO3a-PYGL axis was critical for Se supranutrition-induced lipid accumulation. Moreover, Se supranutrition-induced lipid accumulation was via the increased DNA binding capacity of FOXO3a to PYGL promoter, which increased glycogenolysis, and accordingly promoted lipogenesis and lipid accumulation. Our finding provides new insight into the mechanism of Se supranutrition-induced lipid accumulation and suggests that SELENOF may be a therapeutic target for Se supranutrition induced-lipid disorders in the vertebrates.
Asunto(s)
Glucogenólisis , Selenio , Animales , Lípidos , Lipogénesis/genética , Selenio/farmacología , Selenoproteínas/genéticaRESUMEN
Hypoglycemia causes sex-reliant changes in hypothalamic astrocyte glycogen metabolism in vivo. The role of nuclear versus membrane astrocyte estrogen receptors (ER) in glucoprivic regulation of glycogen is unclear. Here, primary hypothalamic astrocyte cultures were treated with selective ER antagonists during glucoprivation to investigate the hypothesis that ER mediate sex-specific glycogen responses to glucoprivation. Results show that glucoprivic down-regulation of glycogen synthase expression is mediated by transmembrane G protein-coupled ER-1 (GPER) signaling in each sex and estrogen receptor (ER)-beta (ERß) activity in females. Glucoprivic inhibition of glycogen phosphorylase involves GPER and ERß in females, but ER-independent mechanisms in males. GPER, ERß, and ER-alpha (ERα) inhibit or stimulate AMPK protein expression in male versus female astrocytes, respectively. Glucoprivic augmentation of phospho-AMPK profiles in male glia was opposed by GPER activation, whereas GPER and ERß suppress this protein in females. Astrocyte ERα and GPER content was down-regulated in each sex during glucose deficiency, whereas ERß levels was unaltered (males) or increased (females). Glucoprivation correspondingly elevated or diminished male versus female astrocyte glycogen content; ER antagonism reversed this response in males, but not females. Results identify distinctive ER variants involved in sex-similar versus sex-specific astrocyte protein responses to withdrawal of this substrate fuel. Notably, glucoprivation elicits a directional switch or gain-of-effect of GPER and ERß on specific glial protein profiles. Outcomes infer that ERs are crucial for glucoprivic regulation of astrocyte glycogen accumulation in males. Alternatively, estradiol may act independently of ER signaling to disassemble this reserve in females.
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Astrocitos/metabolismo , Glucógeno/metabolismo , Hipoglucemia/metabolismo , Hipotálamo/metabolismo , Animales , Astrocitos/citología , Células Cultivadas , Estradiol/farmacología , Femenino , Glucosa/deficiencia , Glucosa/farmacología , Glucogenólisis/fisiología , Hipotálamo/citología , Masculino , Cultivo Primario de Células , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/fisiología , Caracteres Sexuales , Transducción de Señal/efectos de los fármacosRESUMEN
Glycogen is a branched glucose polymer involved in sustaining blood glucose homeostasis. Liver glycogen comprises α particles (up to 300 nm in diameter) made of joined ß particles (â¼20 nm in diameter). Glycogen α particles in a mouse model for diabetes are molecularly fragile, breaking down into smaller ß particles more readily than in healthy mice. Glycogen phosphorylase (GP), a rate-limiting enzyme in glycogen degradation, is overexpressed in diabetic mice. This study shows that Metformin and Berberine, two common drugs, two common drugs used to treat diabetes, are able to revert the liver glycogen of diabetic mice to the stable structure seen in non-diabetic mice. It is also shown that these drugs reduce the GP level via the cAMP/PKA signaling pathway in diabetic livers and decrease the affinity of GP with the glycogen of db/db mice. These effects of these drugs may slow down the degradation of liver glycogen and improve glucose homeostasis.
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Berberina/uso terapéutico , Diabetes Mellitus Experimental/tratamiento farmacológico , Glucogenólisis/efectos de los fármacos , Hipoglucemiantes/uso terapéutico , Glucógeno Hepático/metabolismo , Metformina/uso terapéutico , Animales , Quimioterapia Combinada , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Glucógeno Hepático/química , Masculino , Ratones , Ratones Endogámicos C57BL , Estructura MolecularRESUMEN
Astrocytes are a unique brain cell-storing glycogen and express lysophosphatidic acid (LPA) receptors. Gintonin is a ginseng-derived exogenous G protein-coupled LPA receptor ligand. Accumulating evidence shows that astrocytes serve as an energy supplier to neurons through astrocytic glycogenolysis under physiological and pathophysiological conditions. However, little is known about the relationships between LPA receptors and astrocytic glycogenolysis or about the roles of LPA receptors in hypoxia and re-oxygenation stresses. In the present study, we examined the functions of gintonin-mediated astrocytic glycogenolysis in adenosine triphosphate (ATP) production, glutamate uptake, and cell viability under normoxic, hypoxic, and re-oxygenation conditions. The application of gintonin or LPA to astrocytes induced glycogenolysis in concentration- and time-dependent manners. The stimulation of gintonin-mediated astrocytic glycogenolysis was achieved through the LPA receptor-Gαq/11 protein-phospholipase C-inositol 1,4,5-trisphosphate receptor-intracellular calcium ([Ca2+]i) transient pathway. Gintonin treatment to astrocytes increased the phosphorylation of brain phosphorylase kinase, with sensitive manner to K252a, an inhibitor of phosphorylase kinase. Gintonin-mediated astrocytic glycogenolysis was blocked by isofagomine, a glycogen phosphorylase inhibitor. Gintonin additionally increased astrocytic glycogenolysis under hypoxic and re-oxygenation conditions. Moreover, gintonin increased ATP production, glutamate uptake, and cell viability under the hypoxic and re-oxygenation conditions. Collectively, we found that the gintonin-mediated [Ca2+]i transients regulated by LPA receptors were coupled to astrocytic glycogenolysis and that stimulation of gintonin-mediated astrocytic glycogenolysis was coupled to ATP production and glutamate uptake under hypoxic and re-oxygenation conditions, ultimately protecting astrocytes. Hence, the gintonin-mediated astrocytic energy that is modulated via LPA receptors helps to protect astrocytes under hypoxia and re-oxygenation stresses.
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Astrocitos/metabolismo , Astrocitos/patología , Glucogenólisis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Oxígeno/farmacología , Panax/química , Receptores del Ácido Lisofosfatídico/metabolismo , Estrés Fisiológico , Adenosina Trifosfato/biosíntesis , Animales , Astrocitos/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Ácido Glutámico/metabolismo , Glucógeno Sintasa/metabolismo , Ligandos , Lisofosfolípidos/farmacología , Ratones , Modelos Biológicos , Transducción de Señal/efectos de los fármacos , Estrés Fisiológico/efectos de los fármacosRESUMEN
A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes.
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Aminoácidos/sangre , Glucosa/metabolismo , Hipotálamo/fisiología , Hígado/metabolismo , Animales , Astrocitos/fisiología , Glucemia/análisis , Grasas de la Dieta/administración & dosificación , Gluconeogénesis/fisiología , Glucogenólisis/fisiología , Homeostasis/fisiología , Humanos , Leucina , Hígado/inervación , Neuronas/fisiología , Prolina/sangre , Nervio Vago/fisiologíaRESUMEN
Ginseng has a long history of use as a tonic for restoration of vigor. One example of ginseng-derived tonic effect is that it can improve physical stamina under conditions of stress. However, the active ingredient and the underlying molecular mechanism responsible for the ergogenic effect are unknown. Recent studies show that ginseng contains a novel ingredient, gintonin, which consists of a unique class of herbal-medicine lysophosphatidic acids (LPAs). Gintonin activates G protein-coupled LPA receptors to produce a transient [Ca(2+)]i signal, which is coupled to diverse intra- and inter-cellular signal transduction pathways that stimulate hormone or neurotransmitter release. However, relatively little is known about how gintonin-mediated cellular modulation is linked to physical endurance. In the present study, systemic administration of gintonin, but not ginsenosides, in fasted mice increased blood glucose concentrations in a dose-dependent manner. Gintonin treatment elevated blood glucose to a maximum level after 30min. This elevation in blood glucose level could be abrogated by the LPA1/3 receptor antagonist, Ki16425, or the ß-adrenergic receptor antagonist, propranolol. Furthermore, gintonin-dependent enhanced performance of fasted mice in rotarod test was likewise abrogated by Ki16425. Gintonin also elevated plasma epinephrine and norepinephrine concentrations. The present study shows that gintonin mediates catecholamine release through activation of the LPA receptor and that activation of the ß-adrenergic receptor is coupled to liver glycogenolysis, thereby increasing the supply of glucose and enhancing performance in the rotarod test. Thus, gintonin acts via the LPA-catecholamine-glycogenolysis axis, representing a candidate mechanism that can explain how ginseng treatment enhances physical stamina.
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Catecolaminas/metabolismo , Actividad Motora/efectos de los fármacos , Extractos Vegetales/farmacología , Receptores del Ácido Lisofosfatídico/metabolismo , Glándulas Suprarrenales/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Animales , Glucemia/metabolismo , Epinefrina/sangre , Ayuno , Glucogenólisis , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Norepinefrina/sangre , Condicionamiento Físico Animal , Resistencia Física/efectos de los fármacos , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
BACKGROUND AND AIM: Zinc oxide (ZnO) and titanium dioxide (TiO2) nanomaterials (NMs) are used in many consumer products, including foodstuffs. Ingested and inhaled NM can reach the liver. Whilst their effects on inflammation, cytotoxicity, genotoxicity and mitochondrial function have been explored, no work has been reported on their impact on liver intermediary metabolism. Our aim was to assess the effects of sub-lethal doses of these materials on hepatocyte intermediary metabolism. MATERIAL AND METHODS: After characterisation, ZnO and TiO2 NM were used to treat C3A cells for 4 hours at concentrations ranging between 0 and 10 µg/cm(2), well below their EC50, before the assessment of (i) glucose production and glycolysis from endogenous glycogen and (ii) gluconeogenesis and glycolysis from lactate and pyruvate (LP). Mitochondrial membrane potential was assessed using JC-10 after 0-40 µg/cm(2) ZnO. qRT-PCR was used to assess phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression. Dihydroethidium (DHE) staining and FACS were used to assess intracellular reactive oxygen species (ROS) concentration. RESULTS: Treatment of cells with ZnO, but not TiO2, depressed mitochondrial membrane potential, leading to a dose-dependent increase in glycogen breakdown by up to 430%, with an increase of both glycolysis and glucose release. Interestingly, gluconeogenesis from LP was also increased, up to 10-fold and correlated with a 420% increase in the PEPCK mRNA expression, the enzyme controlling gluconeogenesis from LP. An intracellular increase of ROS production after ZnO treatment could explain these effects. CONCLUSION: At sub-lethal concentrations, ZnO nanoparticles dramatically increased both gluconeogenesis and glycogenolysis, which warrants further in vivo studies.
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Hepatocitos/efectos de los fármacos , Titanio/toxicidad , Óxido de Zinc/toxicidad , Gluconeogénesis/efectos de los fármacos , Glucogenólisis/efectos de los fármacos , Células Hep G2 , Hepatocitos/metabolismo , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Fosfoenolpiruvato Carboxiquinasa (ATP)/metabolismo , Titanio/química , Óxido de Zinc/químicaRESUMEN
This study aimed to examine the effect of pea fiber (PF) and wheat bran fiber (WF) supplementation in rat metabolism. Rats were assigned randomly to one of three dietary groups and were given a basal diet containing 15% PF, 15% WF, or no supplemental fiber. Urine and plasma samples were analyzed by NMR-based metabolomics. PF significantly increased the plasma levels of 3-hydroxybutyrate, and myo-inositol as well as the urine levels of alanine, hydroxyphenylacetate, phenylacetyglycine, and α-ketoglutarate. However, PF significantly decreased the plasma levels of isoleucine, leucine, lactate, and pyruvate as well as the urine levels of allantoin, bile acids, and trigonelline. WF significantly increased the plasma levels of acetone, isobutyrate, lactate, myo-inositol, and lipids as well as the urine levels of alanine, lactate, dimethylglycine, N-methylniconamide, and α-ketoglutarate. However, WF significantly decreased the plasma levels of amino acids, and glucose as well as the urine levels of acetate, allantoin, citrate, creatine, hippurate, hydroxyphenylacetate, and trigonelline. Results suggest that PF and WF exposure can promote antioxidant activity and can exhibit common systemic metabolic changes, including lipid metabolism, energy metabolism, glycogenolysis and glycolysis metabolism, protein biosynthesis, and gut microbiota metabolism. PF can also decrease bile acid metabolism. These findings indicate that different fiber diet may cause differences in the biofluid profile in rats.
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Fibras de la Dieta/metabolismo , Metaboloma , Pisum sativum/química , Triticum/química , Animales , Metabolismo Energético , Femenino , Glucogenólisis , Glucólisis , Metabolismo de los Lípidos , Espectroscopía de Protones por Resonancia Magnética , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: We have previously demonstrated that central apelin is implicated in the control of peripheral glycemia, and its action depends on nutritional (fast versus fed) and physiological (normal versus diabetic) states. An intracerebroventricular (icv) injection of a high dose of apelin, similar to that observed in obese/diabetic mice, increase fasted glycemia, suggesting (i) that apelin contributes to the establishment of a diabetic state, and (ii) the existence of a hypothalamic to liver axis. Using pharmacological, genetic, and nutritional approaches, we aim at unraveling this system of regulation by identifying the hypothalamic molecular actors that trigger the apelin effect on liver glucose metabolism and glycemia. RESULTS: We show that icv apelin injection stimulates liver glycogenolysis and gluconeogenesis via an over-activation of the sympathetic nervous system (SNS), leading to fasted hyperglycemia. The effect of central apelin on liver function is dependent of an increased production of hypothalamic reactive oxygen species (ROS). These data are strengthened by experiments using lentiviral vector-mediated over-expression of apelin in hypothalamus of mice that present over-activation of SNS associated to an increase in hepatic glucose production. Finally, we report that mice fed a high-fat diet present major alterations of hypothalamic apelin/ROS signaling, leading to activation of glycogenolysis. INNOVATION/CONCLUSION: These data bring compelling evidence that hypothalamic apelin is one master switch that participates in the onset of diabetes by directly acting on liver function. Our data support the idea that hypothalamic apelin is a new potential therapeutic target to treat diabetes.
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Diabetes Mellitus Tipo 2/metabolismo , Glucosa/metabolismo , Hipotálamo/metabolismo , Péptidos y Proteínas de Señalización Intercelular/fisiología , Hígado/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Adipoquinas , Animales , Apelina , Sistema Nervioso Autónomo , Glucemia , Gluconeogénesis , Glucogenólisis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Transducción de SeñalRESUMEN
Citrus aurantium extracts, which contain large amounts of p-synephrine, are widely used for weight loss purposes and as appetite suppressants. In the liver, C. aurantium (bitter orange) extracts affect hemodynamics, carbohydrate metabolism, and oxygen uptake. The purpose of the present work was to quantify the action of p-synephrine and also to obtain indications about its mechanism of action, a task that would be difficult to accomplish with C. aurantium extracts due to their rather complex composition. The experimental system was the isolated perfused rat liver. p-Synephrine significantly stimulated glycogenolysis, glycolysis, gluconeogenesis, and oxygen uptake. The compound also increased the portal perfusion pressure and the redox state of the cytosolic NAD(+)/NADH couple. A Ca(2+)-dependency for both the hemodynamic and the metabolic effects of p-synephrine was found. p-Synephrine stimulated both cAMP overflow and the initial Ca(2+) release from the cellular stores previously labeled with (45)Ca(2+). The metabolic and hemodynamic actions of p-synephrine were strongly inhibited by α-adrenergic antagonists and moderately affected by ß-adrenergic antagonists. The results allow to conclude that p-synephrine presents important metabolic and hemodynamic effects in the liver. These effects can be considered as both catabolic (glycogenolysis) and anabolic (gluconeogenesis), they are mediated by both α- and ß-adrenergic signaling, require the simultaneous participation of both Ca(2+) and cAMP, and could be contributing to the overall stimulation of metabolism that usually occurs during weight loss periods.
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Metabolismo de los Hidratos de Carbono/efectos de los fármacos , Hígado/metabolismo , Consumo de Oxígeno/efectos de los fármacos , Sinefrina/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Antagonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Calcio/metabolismo , Citrus/metabolismo , AMP Cíclico/biosíntesis , Gluconeogénesis/efectos de los fármacos , Glucogenólisis/efectos de los fármacos , Glucólisis/efectos de los fármacos , Masculino , Oxidación-Reducción/efectos de los fármacos , Extractos Vegetales/farmacología , Prazosina/farmacología , Propanolaminas/farmacología , Propranolol/farmacología , Ácido Pirúvico/metabolismo , Ratas , Ratas Wistar , Transducción de Señal , Yohimbina/farmacologíaRESUMEN
The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3ß gene transcription. Thus, central and peripheral insulin action combined to control some, but not other, hepatic enzyme programs. Nevertheless, inhibition of hypothalamic insulin action did not alter the effects of the hormone on hepatic glucose flux (production or uptake). These data indicate that brain insulin action is not a determinant of the rapid (<4 h) inhibition of hepatic glucose metabolism caused by normal physiologic hyperinsulinemia in this large animal model.
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Encéfalo/fisiología , Glucosa/metabolismo , Insulina/fisiología , Hígado/metabolismo , Animales , Perros , Femenino , Glucoquinasa/fisiología , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Glucogenólisis , Hipotálamo/fisiología , Masculino , Fosforilación , Factor de Transcripción STAT3/metabolismoRESUMEN
Gallic acid (GA) and its metabolites are polyphenolic compounds present in daily diets and herbal medicines. To understand the GA effects on the endogenous metabolism of mammals, we systematically analyzed the metabonomic responses of rat plasma, liver, urine, and feces to a single GA dosage of 120 and 600 mg/kg, which were below the no-obvious-adverse-effect-level of 1 g/kg for rats. Clinical chemistry and histopathological assessments were conducted to provide complementary information. Our results showed that GA intake induced significant metabonomic changes in multiple rat biological matrices. Such changes were more outstanding in liver than in the other matrices and clearly showed dose- and time-dependence. The results suggested GA-induced promotion of oxidative stress as the major effect. High-dose GA caused significant metabolic changes involving glycogenolysis, glycolysis, TCA cycle, and metabolism of amino acids, purines, and pyrimidines, together with gut microbiota functions. Low-dose GA only caused some urinary metabonomic changes and to a much less degree. The GA-induced liver metabonomic changes were not completely recoverable within a week, although such recovery completed in plasma, urine, and feces within 80 h. These findings provided new essential information on the effects of dietary polyphenols and demonstrated the great potential of this nutrimetabonomics approach.
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Ácido Gálico/farmacología , Hígado/efectos de los fármacos , Metaboloma , Administración Oral , Aminoácidos/sangre , Aminoácidos/orina , Animales , Ciclo del Ácido Cítrico , Relación Dosis-Respuesta a Droga , Heces/química , Glucogenólisis , Glucólisis , Hígado/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Estrés Oxidativo , Purinas/sangre , Purinas/orina , Pirimidinas/sangre , Pirimidinas/orina , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The fruit extracts of Citrus aurantium (bitter orange) are traditionally used as weight-loss products and as appetite supressants. An important fruit component is p-synephrine, which is structurally similar to the adrenergic agents. Weight-loss and adrenergic actions are always related to metabolic changes and this work was designed to investigate a possible action of the C. aurantium extract on liver metabolism. The isolated perfused rat liver was used to measure catabolic and anabolic pathways, including oxygen uptake and perfusion pressure. The C. aurantium extract and p-synephrine increased glycogenolysis, glycolysis, oxygen uptake and perfusion pressure. These changes were partly sensitive to α- and ß-adrenergic antagonists. p-Synephrine (200 µM) produced an increase in glucose output that was only 15% smaller than the increment caused by the extract containing 196 µM p-synephrine. At low concentrations the C. aurantium extract tended to increase gluconeogenesis, but at high concentrations it was inhibitory, opposite to what happened with p-synephrine. The action of the C. aurantium extract on liver metabolism is similar to the well known actions of adrenergic agents and can be partly attributed to its content in p-synephrine. Many of these actions are catabolic and compatible with the weight-loss effects usually attributed to C. aurantium.
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Citrus/química , Frutas/química , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Sinefrina/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Suplementos Dietéticos , Glucógeno/metabolismo , Glucogenólisis , Glucólisis , Hígado/metabolismo , Técnicas de Cultivo de Órganos , Consumo de Oxígeno/efectos de los fármacos , Perfusión , Ratas , Pérdida de Peso/efectos de los fármacosRESUMEN
Glucagon-like peptide-1 (GLP-1) receptor knockout (Glp1r(-/-)) mice exhibit impaired hepatic insulin action. High fat (HF)-fed Glp1r(-/-) mice exhibit improved, rather than the expected impaired, hepatic insulin action. This is due to decreased lipogenic gene expression and triglyceride accumulation. The present studies overcome these secondary adaptations by acutely modulating GLP-1R action in HF-fed wild-type mice. The central GLP-1R was targeted given its role as a regulator of hepatic insulin action. We hypothesized that acute inhibition of the central GLP-1R impairs hepatic insulin action beyond the effects of HF feeding. We further hypothesized that activation of the central GLP-1R improves hepatic insulin action in HF-fed mice. Insulin action was assessed in conscious, unrestrained mice using the hyperinsulinemic euglycemic clamp. Mice received intracerebroventricular (icv) infusions of artificial cerebrospinal fluid, GLP-1, or the GLP-1R antagonist exendin-9 (Ex-9) during the clamp. Intracerebroventricular Ex-9 impaired the suppression of hepatic glucose production by insulin, whereas icv GLP-1 improved it. Neither treatment affected tissue glucose uptake. Intracerebroventricular GLP-1 enhanced activation of hepatic Akt and suppressed hypothalamic AMP-activated protein kinase. Central GLP-1R activation resulted in lower hepatic triglyceride levels but did not affect muscle, white adipose tissue, or plasma triglyceride levels during hyperinsulinemia. In response to oral but not intravenous glucose challenges, activation of the central GLP-1R improved glucose tolerance. This was associated with higher insulin levels. Inhibition of the central GLP-1R had no effect on oral or intravenous glucose tolerance. These results show that inhibition of the central GLP-1R deteriorates hepatic insulin action in HF-fed mice but does not affect whole body glucose homeostasis. Contrasting this, activation of the central GLP-1R improves glucose homeostasis in HF-fed mice by increasing insulin levels and enhancing hepatic insulin action.
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Péptido 1 Similar al Glucagón/metabolismo , Hipotálamo/metabolismo , Resistencia a la Insulina , Insulina/metabolismo , Hígado/metabolismo , Páncreas/metabolismo , Receptores de Glucagón/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Dieta Alta en Grasa/efectos adversos , Péptido 1 Similar al Glucagón/administración & dosificación , Receptor del Péptido 1 Similar al Glucagón , Técnica de Clampeo de la Glucosa , Glucogenólisis/efectos de los fármacos , Hipotálamo/efectos de los fármacos , Hipotálamo/enzimología , Infusiones Intraventriculares , Insulina/sangre , Secreción de Insulina , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/metabolismo , Especificidad de Órganos , Páncreas/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Glucagón/agonistas , Receptores de Glucagón/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
Arginine vasopressin (AVP) is a neuropeptide with vasoconstrictive, antidiuretic, cardiovascular regulative and hepatic glycogenolysis effects, that also affects other behaviors including modulating learning. A number of studies on AVP regulation have been conducted in various metabolic diseases (disorders). In this study, the immunoreactivities of AVP in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) and mRNA expressions in the hypothalamus were investigated by immunohistochemistry and quantitative real-time PCR (RT-qPCR) in stroke-prone spontaneously hypertensive rats at different ages (i.e., at postnatal months [PM] 1, 8, and 12). Blood glucose levels in the PM 8 group were higher than in the other groups. However, cresyl violet positive neurons were detected in the PVN and SON of all animals, and numbers of cresyl violet positive neurons were similar in all aged groups. In addition, AVP immunoreactivity was detected in the PVN and SON of all age groups, and AVP immunoreactivity and mRNA expression levels were found to be increased in proportion to age by immunohistochemistry and RT-qPCR. These results suggest that the diabetic condition is temporally generated after hypertension has developed. Furthermore, our findings suggest that increased AVP expressions in the hypothalamic PVN and SON are associated with hypertension by age.
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Anciano , Animales , Humanos , Arginina , Arginina Vasopresina , Benzoxazinas , Glucemia , Glucogenólisis , Hipertensión , Hipotálamo , Inmunohistoquímica , Aprendizaje , Enfermedades Metabólicas , Molibdeno , Neuronas , Neuropéptidos , Óxidos , Núcleo Hipotalámico Paraventricular , Ratas Endogámicas SHR , Reacción en Cadena en Tiempo Real de la Polimerasa , ARN Mensajero , Núcleo Supraóptico , ViolaRESUMEN
Juglone is a phenolic compound used in popular medicine as a phytotherapic to treat inflammatory and infectious diseases. However, it also acts as an uncoupler of oxidative phosphorylation in isolated liver mitochondria and, thus, may interfere with the hepatic energy metabolism. The purpose of this work was to evaluate the effect of juglone on several metabolic parameters in the isolated perfused rat liver. Juglone, in the concentration range of 5 to 50µM, stimulated glycogenolysis, glycolysis and oxygen uptake. Gluconeogenesis from both lactate and alanine was inhibited with half-maximal effects at the concentrations of 14.9 and 15.7µM, respectively. The overall alanine transformation was increased by juglone, as indicated by the stimulated release of ammonia, urea, l-glutamate, lactate and pyruvate. A great increase (9-fold) in the tissue content of α-ketoglutarate was found, without a similar change in the l-glutamate content. The tissue contents of ATP were decreased, but those of ADP and AMP were increased. Experiments with isolated mitochondria fully confirmed previous notions about the uncoupling action of juglone. It can be concluded that juglone is active on metabolism at relatively low concentrations. In this particular it resembles more closely the classical uncoupler 2,4-dinitrophenol. Ingestion of high doses of juglone, thus, presents the same risks as the ingestion of 2,4-dinitrophenol which comprise excessive compromising of ATP production, hyperthermia and even death. Low doses, i.e., moderate consumption of natural products containing juglone, however, could be beneficial to health if one considers recent reports about the consequences of chronic mild uncoupling.
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Metabolismo Energético/efectos de los fármacos , Hígado/efectos de los fármacos , Mitocondrias Hepáticas/efectos de los fármacos , Naftoquinonas/toxicidad , Consumo de Oxígeno/efectos de los fármacos , 2,4-Dinitrofenol/toxicidad , Adenosina Trifosfato/metabolismo , Alanina/efectos de los fármacos , Alanina/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Glucogenólisis/efectos de los fármacos , Glucólisis/efectos de los fármacos , Hígado/metabolismo , Masculino , Mitocondrias Hepáticas/metabolismo , Naftoquinonas/administración & dosificación , Ratas , Ratas WistarRESUMEN
SCOPE: Research reports suggest that vitamin D affects glucose and insulin metabolism; however, the exact mechanisms are unclear. ²H NMR analysis of monoacetone glucose (MAG) after tracer administration provides a non-invasive method of profiling hepatic glucose metabolism. This study examined the effects of supplementation with vitamin D3 on contribution of glycogenolysis to glucose production. METHODS AND RESULTS: Tracer administration and biofluid collections were performed with eight healthy females before and following a 4-wk vitamin D3 administration period. Following an overnight fast subjects ingested deuterated water and acetaminophen. Full void urine samples were collected after 4 h. ²H NMR spectra of urinary monoacetone glucose were acquired to determine the contribution of glycogenolysis to glucose production. The mean contribution of glycogenolysis to glucose production was 60±13%. Supplementation with vitamin D3 had no effect on hepatic glucose production. Regression analysis revealed a significant relationship between carbohydrate intake and the contribution of glycogenolysis (ß=0.914, p=0.004). CONCLUSION: In conclusion, we saw no changes in the percentage contribution of glycogenolysis following supplementation with vitamin D3. The reproducibility of our results and the non-invasive nature of the method highlight the potential for this method in assessing mechanistic modes of action in future nutritional interventions.
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Colecalciferol/farmacología , Glucosa/metabolismo , Hígado/metabolismo , Adulto , Deuterio , Suplementos Dietéticos , Femenino , Glucosa/análogos & derivados , Glucosa/análisis , Glucogenólisis/efectos de los fármacos , Glucogenólisis/fisiología , Humanos , Hígado/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Trazadores Radiactivos , Análisis de RegresiónRESUMEN
Contributions of gluconeogenesis suppression in liver, kidney, and intestine as major gluconeogenic organs to the glucose-lowering effect of CS-917, a fructose 1,6-bisphosphatase inhibitor, was evaluated in overnight-fasted Goto-Kakizaki (GK) rats. CS-917 decreased plasma glucose by suppressing glucose release and lactate uptake from liver but not from kidney and intestine. These results suggest that hepatic gluconeogenesis suppression predominantly contributes to the glucose-lowering effect of CS-917 in GK rats. Moreover, the mechanism by which CS-917 decreased plasma glucose more in overnight-fasted GK rats than in non-fasted ones was investigated. Lactate uptake from liver was suppressed by 15 mg/kg of CS-917 in both states, but glucose release from liver and plasma glucose were decreased only in the overnight-fasted state. CS-917 at 30 mg/kg decreased hepatic glycogen content in both states and depleted it in the overnight-fasted state. In the non-fasted GK rats, co-administration of CS-917 with CP-91149, a glycogen phosphorylase inhibitor, suppressed hepatic glycogen reduction by CS-917 and decreased plasma glucose more than single administration of CS-917. These results suggest that gluconeogenesis suppression by CS-917 was counteracted by hepatic glycogenolysis especially in the non-fasted state and that combination therapy with CS-917 and CP-91149 is efficacious to decrease plasma glucose in GK rats.
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Alanina/análogos & derivados , Amidas/farmacología , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Gluconeogénesis/efectos de los fármacos , Glucogenólisis/efectos de los fármacos , Hipoglucemiantes/farmacología , Indoles/farmacología , Compuestos Organofosforados/farmacología , Alanina/farmacología , Animales , Evaluación Preclínica de Medicamentos , Ayuno/fisiología , Glucosa/metabolismo , Ácido Láctico/metabolismo , Masculino , Organofosfonatos , Péptido Hidrolasas/metabolismo , RatasAsunto(s)
Neuropatías Diabéticas/metabolismo , Neuropatías Diabéticas/terapia , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/terapia , Terapia por Acupuntura , Aldehído Reductasa/metabolismo , Analgésicos/uso terapéutico , Descompresión Quirúrgica , Neuropatías Diabéticas/diagnóstico , Electromiografía , Glucogenólisis , Humanos , Anamnesis , Síndromes de Compresión Nerviosa/complicaciones , Síndromes de Compresión Nerviosa/diagnóstico , Síndromes de Compresión Nerviosa/terapia , Conducción Nerviosa , Examen Neurológico , Aparatos Ortopédicos , Traumatismos de los Nervios Periféricos , Nervios Periféricos/metabolismo , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Estimulación Eléctrica Transcutánea del NervioRESUMEN
Higher fat and lower carbohydrate and amino acid oxidation are observed in women compared with men during endurance exercise. We hypothesized that the observed sex difference is due to estrogen and that menstrual cycle phase or supplementation of men with 17beta-estradiol (E(2)) would coordinately influence the mRNA content of genes involved in lipid and/or carbohydrate metabolism in skeletal muscle. Twelve men and twelve women had muscle biopsies taken before and immediately after 90 min of cycling at 65% peak oxygen consumption (Vo(2peak)). Women were studied in the midfollicular (Fol) and midluteal (Lut) phases, and men were studied after 8 days of E(2) or placebo supplementation. Targeted RT-PCR was used to compare mRNA content for genes involved in transcriptional regulation and lipid, carbohydrate, and amino acid metabolism. Sex was the greatest predictor of substrate metabolism gene content. Sex affected the mRNA content of FATm, FABPc, SREBP-1c, mtGPAT, PPARdelta, PPARalpha, CPTI, TFP-alpha, GLUT4, HKII, PFK, and BCOADK (P < 0.05). E(2) administration significantly (P < 0.05) affected the mRNA content of PGC-1alpha, PPARalpha, PPARdelta, TFP-alpha, CPTI, SREBP-1c, mtGPAT, GLUT4, GS-1, and AST. Acute exercise increased the mRNA abundance for PGC-1alpha, HSL, FABPc, CPTI, GLUT4, HKII, and AST (P < 0.05). Menstrual cycle had a small effect on PPARdelta, GP, and glycogenin mRNA content. Overall, women have greater mRNA content for several genes involved in lipid metabolism, which is partially due to an effect of E(2).