Storage and Utilization of Glycogen by Mouse Liver during Adaptation to Nutritional Changes Are GLP-1 and PASK Dependent

Glucagon-like peptide 1 (GLP-1) and PAS kinase (PASK) control glucose and energy homeostasis according to nutritional status. Thus, both glucose availability and GLP-1 lead to hepatic glycogen synthesis or degradation. We used a murine model to discover whether PASK mediates the effect of exendin-4 (GLP-1 analogue) in the adaptation of hepatic glycogen metabolism to nutritional status. The results indicate that both exendin-4 and fasting block the Pask expression, and PASK deficiency disrupts the physiological levels of blood GLP1 and the expression of hepatic GLP1 receptors after fasting. Under a non-fasted state, exendin-4 treatment blocks AKT activation, whereby Glucokinase and Sterol Regulatory Element-Binding Protein-1c (Srebp1c) expressions were inhibited. Furthermore, the expression of certain lipogenic genes was impaired, while increasing Glucose Transporter 2 (GLUT2) and Glycogen Synthase (GYS). Moreover, exendin-4 treatment under fasted conditions avoided Glucose 6-Phosphatase (G6pase) expression, while maintaining high GYS and its activation state. These results lead to an abnormal glycogen accumulation in the liver under fasting, both in PASK-deficient mice and in exendin-4 treated wild-type mice. In short, exendin-4 and PASK both regulate glucose transport and glycogen storage, and some of the exendin-4 effects could therefore be due to the blocking of the Pask expression.

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Adiponectin regulates glycogen metabolism at the human fetal–maternal interface

Journal of Molecular Endocrinology ◽

10.1530/jme-18-0013 ◽

2018 ◽

Vol 61 (3) ◽

pp. 139-152 ◽

Cited By ~ 3

Author(s):

Fabien Duval ◽

Esther Dos Santos ◽

Benoît Maury ◽

Valérie Serazin ◽

Khadija Fathallah ◽

...

Keyword(s):

Molecular Mechanisms ◽

Glucose Transporter ◽

Glycogen Synthesis ◽

Critical Role ◽

Glycogen Metabolism ◽

First Trimester ◽

Endometrial Stromal Cells ◽

Glucose Transporter 1 ◽

Glycogen Accumulation ◽

First Trimester Of Pregnancy

Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal–maternal interface have not yet been characterized. Among the various factors acting at the fetal–maternal interface, we focused on adiponectin – an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal–maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta.

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Heating after intense repeated contractions inhibits glycogen accumulation in mouse EDL muscle: role of phosphorylase in postexercise glycogen metabolism

AJP Cell Physiology ◽

10.1152/ajpcell.00315.2018 ◽

2018 ◽

Vol 315 (5) ◽

pp. C706-C713 ◽

Cited By ~ 1

Author(s):

Sarah J. Blackwood ◽

Ester Hanya ◽

Abram Katz

Keyword(s):

Glycogen Synthase ◽

Glycogen Synthesis ◽

Glycogen Metabolism ◽

Type Ii ◽

Muscle Type ◽

Phosphorylase Activity ◽

Glycogen Accumulation ◽

Longus Muscle ◽

Edl Muscle

The effects of heating on glycogen synthesis (incorporation of [14C]glucose into glycogen) and accumulation after intense repeated contractions were investigated. Isolated mouse extensor digitorum longus muscle (type II) was stimulated electrically to perform intense tetanic contractions at 25°C. After 120 min recovery at 25°C, glycogen accumulated to almost 80% of basal, whereas after recovery at 35°C, glycogen remained low (~25% of basal). Glycogen synthesis averaged 0.97 ± 0.07 µmol·30 min−1·g wet wt−1 during recovery at 25°C and 1.48 ± 0.08 during recovery at 35°C ( P < 0.001). There were no differences in phosphorylase and glycogen synthase total activities nor in phosphorylase fractional activity, whereas glycogen synthase fractional activity was increased by ~50% after recovery at 35°C vs. 25°C. Inorganic phosphate (Pi, substrate for phosphorylase) was markedly increased (~300% of basal) following contraction but returned to control levels after 120 min recovery at 25°C. In contrast, Pi remained elevated after recovery at 35°C (>2-fold higher than recovery at 25°C). Estimates of glycogen breakdown indicated that phosphorylase activity (either via inhibition at 25°C or activation at 35°C) was responsible for ~60% of glycogen accumulation during recovery at 25°C and ~45% during recovery at 35°C. These data demonstrate that despite the enhancing effect of heating on glycogen synthesis during recovery from intense contractions, glycogen accumulation is inhibited owing to Pi-mediated activation of phosphorylase. Thus phosphorylase can play a quantitatively important role in glycogen biogenesis during recovery from repeated contractions in isolated type II muscle.

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Astrocytic glycogen accumulation drives the pathophysiology of neurodegeneration in Lafora disease

Brain ◽

10.1093/brain/awab110 ◽

2021 ◽

Author(s):

Jordi Duran ◽

Arnau Hervera ◽

Kia H Markussen ◽

Olga Varea ◽

Iliana López-Soldado ◽

...

Keyword(s):

Mouse Model ◽

Neurodegenerative Disorder ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Glycogen Metabolism ◽

Cell Type ◽

Lafora Disease ◽

Glycogen Accumulation ◽

Lafora Bodies

Abstract The hallmark of Lafora disease, a fatal neurodegenerative disorder, is the accumulation of intracellular glycogen aggregates, called Lafora bodies. Until recently, it was widely believed that brain Lafora bodies were present exclusively in neurons and thus that Lafora disease pathology derived from their accumulation in this cell population. However, recent evidence indicates that Lafora bodies are also present in astrocytes. To define the role of astrocytic Lafora bodies in Lafora disease pathology, we deleted glycogen synthase specifically from astrocytes in a mouse model of the disease (malinKO). Strikingly, blocking glycogen synthesis in astrocytes—thus impeding Lafora bodies accumulation in this cell type—prevented the increase in neurodegeneration markers, autophagy impairment, and metabolic changes characteristic of the malinKO model. Conversely, mice that overaccumulate glycogen in astrocytes showed an increase in these markers. These results unveil the deleterious consequences of the deregulation of glycogen metabolism in astrocytes and change the perspective that Lafora disease is caused solely by alterations in neurons.

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Association of glycogen synthase phosphatase and phosphorylase phosphatase activities with membranes of hepatic smooth endoplasmic reticulum.

The Journal of Cell Biology ◽

10.1083/jcb.83.2.348 ◽

1979 ◽

Vol 83 (2) ◽

pp. 348-356 ◽

Cited By ~ 31

Author(s):

R N Margolis ◽

R R Cardell ◽

R T Curnow

Keyword(s):

Endoplasmic Reticulum ◽

Glycogen Synthase ◽

Close Contact ◽

Smooth Endoplasmic Reticulum ◽

Glycogen Synthesis ◽

Glycogen Metabolism ◽

Hepatic Glycogen ◽

Phosphatase Activities ◽

Regulatory Enzymes ◽

Glycogen Particles

A detailed investigation was conducted to determine the precise subcellular localization of the rate-limiting enzymes of hepatic glycogen metabolism (glycogen synthase and phosphorylase) and their regulatory enzymes (synthase phosphatase and phosphorylase phosphatase). Rat liver was homogenized and fractionated to produce soluble, rough and smooth microsomal fractions. Enzyme assays of the fractions were performed, and the results showed that glycogen synthase and phosphorylase were located in the soluble fraction of the livers. Synthase phosphatase and phosphorylase phosphatase activities were also present in soluble fractions, but were clearly identified in both rough and smooth microsomal fractions. It is suggested that the location of smooth endoplasmic reticulum (SER) within the cytosome forms a microenvironment within hepatocytes that establishes conditions necessary for glycogen synthesis (and degradation). Thus the location of SER in the cell determines regions of the hepatocyte that are rich in glycogen particles. Furthermore, the demonstration of the association of synthase phosphatase and phosphorylase phosphatase with membranes of SER may account for the close morphological association of SER with glycogen particles (i.e., disposition of SER membranes brings the membrane-bound regulatory enzymes in close contact with their substrates).

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Interrelationship of glycogen metabolism and lactose synthesis in mammary epithelial cells of mice

Biochemical Journal ◽

10.1042/bj1920695 ◽

1980 ◽

Vol 192 (2) ◽

pp. 695-702 ◽

Cited By ~ 14

Author(s):

J T Emerman ◽

J C Bartley ◽

M J Bissell

Keyword(s):

Epithelial Cells ◽

Mammary Epithelial Cells ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Late Pregnancy ◽

Glycogen Metabolism ◽

Mouse Mammary Gland ◽

Mammary Epithelial ◽

Glycogen Accumulation ◽

Lactose Synthesis

Glycogen metabolism in mammary epithelial cells was investigated (i) by studying the conversion of glucose into glycogen and other cellular products in these cells from virgin, pregnant and lactating mice and (ii) by assaying the enzymes directly involved with glycogen metabolism. We find that: (1) mammary epithelial cells synthesized glycogen at rates up to over 60% that of the whole gland; (2) the rate of this synthesis was modulated greatly during the reproductive cycle, reaching a peak in late pregnancy and decreasing rapidly at parturition, when abundant synthesis of lactose was initiated; (3) glycogen synthase and phosphorylase activities reflected this modulation in glycogen metabolism; (4) lactose synthesis reached a plateau during late pregnancy, even though lactose synthase is reported to increase in the mouse mammary gland at this time. We propose that glycogen synthesis restricts lactose synthesis during late pregnancy by competing successfully for the shared UDP-glucose pool. The physiological advantage of glycogen accumulation during late pregnancy is discussed.

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Morphometric analysis and autoradiography of the smooth endoplasmic reticulum during glycogen deposition in the fetal mouse hepatocyte

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100160273 ◽

1990 ◽

Vol 48 (3) ◽

pp. 544-545

Author(s):

Joanette Shockey Breslin ◽

Robert R. Cardell

Keyword(s):

Endoplasmic Reticulum ◽

Morphometric Analysis ◽

Smooth Endoplasmic Reticulum ◽

Glycogen Synthesis ◽

Glycogen Metabolism ◽

Hepatic Glycogen ◽

Thin Sections ◽

Glycogen Accumulation ◽

Fetal Mouse ◽

Glycogen Deposition

Analyses of adult hepatic glycogen deposition by numerous investigators have determined that the smooth endoplasmic reticulum (SER) proliferates immediately prior to glycogen deposition and during the early stages of glycogen accumulation, then decreases as glycogen levels reach their maximum, suggesting that SER participates in adult hepatic glycogen metabolism. Less is known regarding fetal hepatic glycogen synthesis and the participation of the fetal SER. The studies described here test the hypothesis that the SER functions in the synthesis of fetal hepatic glycogen. Quantitative analysis of SER and glycogen levels during hepatic glycogen synthesis tests the existence of a correlation between glycogen and SER. Newly deposited labeled glycogen is localized via autoradiography and the extent of association between labeled glycogen and SER quantified, establishing whether glycogen is necessarily deposited near membranes of SER.Fetal mouse livers were harvested at daily intervals between days 14 and 19 of gestation, immersion fixed in 2% glutaraldehyde, 2% paraformaldehyde, post-fixed in 1 % OsO4 dehydrated in EtOH and embedded in Epon 812. Semi-thin (0.5μm) and ultra-thin sections (60 nm) were prepared for morphometric analysis.2

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Assessment of the Phenolic Profiles, Hypoglycemic Activity, and Molecular Mechanism of Different Highland Barley (Hordeum vulgare L.) Varieties

International Journal of Molecular Sciences ◽

10.3390/ijms21041175 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1175 ◽

Cited By ~ 3

Author(s):

Na Deng ◽

Bisheng Zheng ◽

Tong Li ◽

Rui Hai Liu

Keyword(s):

Molecular Mechanism ◽

Phosphoenolpyruvate Carboxykinase ◽

Glucose Transporter ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Hypoglycemic Activity ◽

Hordeum Vulgare L ◽

Glycogen Accumulation ◽

Phenolic Profiles ◽

Highland Barley

The phenolic profiles, hypoglycemic activity, and molecular mechanism of the effect on type 2 diabetes mellitus (T2DM) of four highland barley varieties were investigated in the present study. The fundamental phenolics in highland barley were ferulic acid, naringin, and catechin, which mainly existed in bound form. These varieties showed favorable hypoglycemic activity via inhibition of α-glucosidase and α-amylase activities, enhancement of glucose consumption, glycogen accumulation and glycogen synthase 2 (GYS2) activity, and down-regulation of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities. Specifically, ZQ320 variety exhibited the strongest hypoglycemic activity compared to the other varieties. Highland barley phenolics could inhibit gluconeogenesis and motivate glycogen synthesis via down-regulating the gene expression of G6Pase, PEPCK, and glycogen synthase kinase 3β (GSK3β), while activating the expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3 kinase (PI3K), serine/threonine kinase (Akt), GYS2, and glucose transporter type 4 (GLUT4). Therefore, phenolics from highland barley could be served as suitable candidates for therapeutic agent in T2DM to improve human health.

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Egg oil from Portunus trituberculatus alleviates insulin resistance through activation of insulin signaling in mice

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2018-0718 ◽

2019 ◽

Vol 44 (10) ◽

pp. 1081-1088 ◽

Cited By ~ 3

Author(s):

Shiwei Hu ◽

Jingfeng Wang ◽

Xiaojun Yan ◽

Huicheng Yang ◽

Shijie Li ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Transporter ◽

Glycogen Synthase ◽

Glycogen Synthesis ◽

Animal Experiments ◽

Portunus Trituberculatus ◽

Hepatic Glycogen ◽

Transcriptional Level ◽

Protective Effects ◽

Bioactive Lipids

Marine bioactive lipids have been utilized to overcome insulin resistance. However, oil from swimming crab has never been studied. Here, we analyzed the constituents of egg oil from Portunus trituberculatus (Pt-egg oil) and investigated its protective effects against insulin resistance in mice on a high-fat diet. The results showed that Pt-egg oil contained 52.05% phospholipids, 8.61% free fatty acids (especially eicosapentaenoic acid and docosahexaenoic acid), 32.38% triglyceride, 4.79% total cholesterol, and ditissimus astaxanthin. Animal experiments showed that Pt-egg oil significantly mitigated insulin resistance and was associated with reductions in blood glucose, insulin, glucose tolerance, insulin tolerance, serum lipids, and hepatic glycogen. Pt-egg oil activated the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (Akt)/glucose transporter 4 pathway in skeletal muscle both at the transcriptional level and at the translational level. Pt-egg oil also promoted hepatic glycogen synthesis through activation of the PI3K/Akt/glycogen synthase kinase-3 beta pathway. These indicate that Pt-egg oil can be used as an alternative to marine bioactive lipids to improve insulin resistance.

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Chronic suppression of insulin by diazoxide alters the activities of key enzymes regulating hepatic gluconeogenesis in Zucker rats

Acta Endocrinologica ◽

10.1530/eje.0.1460871 ◽

2002 ◽

pp. 871-879 ◽

Cited By ~ 24

Author(s):

R Alemzadeh ◽

S Holshouser ◽

P Massey ◽

J Koontz

Keyword(s):

Phosphoenolpyruvate Carboxykinase ◽

Glucose Transporter ◽

Glycogen Synthase ◽

Zucker Rats ◽

Hepatic Glycogen ◽

Hepatic Gluconeogenesis ◽

Key Enzymes ◽

Glucose Transporter 2 ◽

Obese Rats ◽

Obese Zucker Rats

OBJECTIVES: Chronic attenuation of hyperinsulinemia by diazoxide (DZ), an inhibitor of glucose-mediated insulin secretion, improved insulin sensitivity and glucose tolerance and caused down-regulation of lipid metabolizing enzymes in adipose tissue and decreased the rate of weight gain in mildly hyperglycemic obese Zucker rats. Since the liver plays a central role in glucose homeostasis, we studied the effect of chronic insulin suppression on key insulin-sensitive enzymes regulating hepatic gluconeogenesis. METHODS: DZ (150 mg/kg per day) or vehicle (control) was administered to 7-week-old female obese and lean Zucker rats for a period of 4 weeks. RESULTS: DZ-treated animals showed lower fasting plasma insulin levels (P<0.001) than their controls. Plasma glucose levels were lower in DZ obese rats than in controls (P<0.001), without a significant change in DZ lean animals. DZ had no effect on glucose transporter 2 protein expression in either strain. DZ treatment resulted in lower hepatic glucokinase (P<0.001) and glucose-6-phosphatase (P<0.0001) and phosphoenolpyruvate carboxykinase (PEPCK) activities only in obese rats compared with controls (P<0.001). However, DZ-treated lean rats demonstrated higher PEPCK activity than controls (P<0.002). DZ-treated animals demonstrated enhanced hepatic glucose-6-phosphate content (P<0.01), glycogen synthase activity (P<0.0001) and glycogen content (P<0.02) compared with their controls despite increased hepatic glycogen phosphorylase a activity in these animals (P<0.02). CONCLUSIONS: Chronic suppression of hyperinsulinemia in obese Zucker rats by DZ decreased the activities of key enzymes regulating hepatic gluconeogenesis, implying that attenuation of the hyperinsulinemic state by DZ may be therapeutically beneficial.

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Catestatin reduces hyperglycemia in insulin-resistant mice by redirecting glucose-6-phosphate from the gluconeogenic to the glycogenic pathway

10.1101/2020.10.31.363481 ◽

2020 ◽

Author(s):

Gautam Bandyopadhyay ◽

Kechun Tang ◽

Nicholas J.G. Webster ◽

Geert van den Bogaart ◽

Sushil K. Mahata

Keyword(s):

Glycogen Synthase ◽

Glycogen Synthesis ◽

Glucose Production ◽

Liver Glycogen ◽

Hepatic Glycogen ◽

Cultured Hepatocytes ◽

Glycogen Accumulation ◽

Insulin Resistant ◽

Glucose Levels ◽

Gsk 3Β

AbstractObjectiveDefects in hepatic glycogen synthesis contribute to postprandial hyperglycemia in type 2 diabetic (T2D) patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352-372) inhibits dephosphorylation of glucose 6-phosphate (G6P) and improves glucose tolerance in insulin-resistant mice. Here, we seek to determine whether CST also reduces hyperglycemia by increasing hepatic glycogen synthesis.MethodsWe determined liver glycogen, G6P, and UDP glucose (UDPG); plasma insulin, glucagon, norepinephrine (NE), and epinephrine (EPI) levels, and glycogen synthase (GYS) activities in fed and fasted liver of lean and obese wild-type and genetically obese CST knockout (KO) mice after treatments with saline, CST or insulin. We determined glycogen synthesis and glycogenolysis in cultured hepatocytes. We analyzed phosphorylation signals of GYS2 and GSK-3β by immunoblotting.ResultsCST stimulated glycogen accumulation in fed and fasted liver and in cultured hepatocytes. CST reduced plasma NE and EPI levels, suggesting that CST promotes glycogenesis by inhibiting catecholamine-induced glycogenolysis. CST also directly stimulated glycogenesis and inhibited NE and EPI-induced glycogenolysis in hepatocytes. CST elevated the levels of G6P and UDPG and increased GYS activity, thus redirecting G6P to the glycogenic pathway. CST-KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role that CST plays in hepatic glycogenesis.ConclusionsWe conclude that CST directly promotes the glycogenic pathway and reduces plasma glucose levels in insulin-resistant mice by (i) reducing glucose production from G6P, (ii) increasing glycogen synthesis from G6P via formation of UDPG, and (iii) reducing glycogenolysis.

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