scholarly journals Central Role for Protein Targeting to Glycogen in the Maintenance of Cellular Glycogen Stores in 3T3-L1 Adipocytes

2006 ◽  
Vol 26 (1) ◽  
pp. 334-342 ◽  
Author(s):  
Cynthia C. Greenberg ◽  
Arpad M. Danos ◽  
Matthew J. Brady
Keyword(s):  
Protein Targeting ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Critical Role ◽  
Glycogen Metabolism ◽  
Metabolizing Enzymes ◽  
Protein Levels ◽  
Extracellular Glucose ◽  
Interfering Rna ◽  
Glycogen Stores

ABSTRACT Overexpression of the protein phosphatase 1 (PP1) subunit protein targeting to glycogen (PTG) markedly enhances cellular glycogen levels. In order to disrupt the endogenous PTG-PP1 complex, small interfering RNA (siRNA) constructs against PTG were identified. Infection of 3T3-L1 adipocytes with PTG siRNA adenovirus decreased PTG mRNA and protein levels by >90%. In parallel, PTG reduction resulted in a >85% decrease in glycogen levels 4 days after infection, supporting a critical role for PTG in glycogen metabolism. Total PP1, glycogen synthase, and GLUT4 levels, as well as insulin-stimulated signaling cascades, were unaffected. However, PTG knockdown reduced glycogen-targeted PP1 protein levels, corresponding to decreased cellular glycogen synthase- and phosphorylase-directed PP1 activity. Interestingly, GLUT1 levels and acute insulin-stimulated glycogen synthesis rates were increased two- to threefold, and glycogen synthase activation in the presence of extracellular glucose was maintained. In contrast, glycogenolysis rates were markedly increased, suggesting that PTG primarily acts to suppress glycogen breakdown. Cumulatively, these data indicate that disruption of PTG expression resulted in the uncoupling of PP1 activity from glycogen metabolizing enzymes, the enhancement of glycogenolysis, and a dramatic decrease in cellular glycogen levels. Further, they suggest that reduction of glycogen stores induced cellular compensation by several mechanisms, but ultimately these changes could not overcome the loss of PTG expression.

scholarly journals Sequestration of host metabolism by an intracellular pathogen

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lena Gehre ◽  
Olivier Gorgette ◽  
Stéphanie Perrinet ◽  
Marie-Christine Prevost ◽  
Mathieu Ducatez ◽  
...  
Keyword(s):  
De Novo ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Strong Support ◽  
Glycogen Metabolism ◽  
Metabolism Enzymes ◽  
The Cost ◽  
Type 3 ◽  
Glycogen Stores ◽  
Host Metabolism

For intracellular pathogens, residence in a vacuole provides a shelter against cytosolic host defense to the cost of limited access to nutrients. The human pathogen Chlamydia trachomatis grows in a glycogen-rich vacuole. How this large polymer accumulates there is unknown. We reveal that host glycogen stores shift to the vacuole through two pathways: bulk uptake from the cytoplasmic pool, and de novo synthesis. We provide evidence that bacterial glycogen metabolism enzymes are secreted into the vacuole lumen through type 3 secretion. Our data bring strong support to the following scenario: bacteria co-opt the host transporter SLC35D2 to import UDP-glucose into the vacuole, where it serves as substrate for de novo glycogen synthesis, through a remarkable adaptation of the bacterial glycogen synthase. Based on these findings we propose that parasitophorous vacuoles not only offer protection but also provide a microorganism-controlled metabolically active compartment essential for redirecting host resources to the pathogens.

scholarly journals Scaffolding protein IQ motif containing GTPase activating protein 2 (IQGAP2) regulates glycogen metabolism

2020 ◽  
Author(s):  
Anushna Sen ◽  
Sara Youssef ◽  
Karen Wendt ◽  
Sayeepriyadarshini Anakk
Keyword(s):  
Metabolic Response ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Scaffolding Protein ◽  
Gtpase Activating Protein ◽  
Fed State ◽  
Iq Motif ◽  
Protein Levels ◽  
Expression Of Genes

AbstractThe liver is critical in maintaining metabolic homeostasis, regulating both anabolic and catabolic processes of fats, proteins, and carbohydrates. The IQ motif containing GTPase activating protein 2 (IQGAP2) is a member of the IQGAP family. Of the three homologous isoforms, the IQGAP2 scaffolding protein is predominantly found in the liver. To characterize its role in regulating metabolism, Iqgap2−/− female and male mice, and their WT controls, were fed ad libitum or fasted for 24 hours. Hepatic gene expression, protein levels, and the metabolic response were compared between WT and Iqgap2−/− mice, using RT-qPCR, western blot analysis, and histological stains. We found that loss of IQGAP2 alters the phosphorylation of active glycogen synthase kinase 3 (GSK3) expression, a known regulator of glycogen synthesis and lipogenesis. Consistent with this result, Iqgap2−/− female mice displayed depletion of periportal glycogen even in the fed state. We also observed the blunted expression of genes involved in glycogenesis and lipogenesis when IQGAP2 was deleted. Since GSK3 is known to regulate the activity of β-catenin, we examined and found it to be reduced in Iqgap2−/− mice. Our findings demonstrate that IQGAP2 plays an important role in regulating glycogen synthesis.

scholarly journals Antagonistic Controls of Autophagy and Glycogen Accumulation by Snf1p, the Yeast Homolog of AMP-Activated Protein Kinase, and the Cyclin-Dependent Kinase Pho85p

2001 ◽  
Vol 21 (17) ◽  
pp. 5742-5752 ◽  
Author(s):  
Zhong Wang ◽  
Wayne A. Wilson ◽  
Marie A. Fujino ◽  
Peter J. Roach
Keyword(s):  
Protein Kinase ◽  
Stationary Phase ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Storage ◽  
Wild Type ◽  
Gene Encoding ◽  
Glycogen Accumulation ◽  
Yeast Homolog ◽  
Glycogen Stores

ABSTRACT In the yeast Saccharomyces cerevisiae, glycogen is accumulated as a carbohydrate reserve when cells are deprived of nutrients. Yeast mutated in SNF1, a gene encoding a protein kinase required for glucose derepression, has diminished glycogen accumulation and concomitant inactivation of glycogen synthase. Restoration of synthesis in an snf1 strain results only in transient glycogen accumulation, implying the existence of otherSNF1-dependent controls of glycogen storage. A genetic screen revealed that two genes involved in autophagy, APG1and APG13, may be regulated by SNF1. Increased autophagic activity was observed in wild-type cells entering the stationary phase, but this induction was impaired in ansnf1 strain. Mutants defective for autophagy were able to synthesize glycogen upon approaching the stationary phase, but were unable to maintain their glycogen stores, because subsequent synthesis was impaired and degradation by phosphorylase, Gph1p, was enhanced. Thus, deletion of GPH1 partially reversed the loss of glycogen accumulation in autophagy mutants. Loss of the vacuolar glucosidase, SGA1, also protected glycogen stores, but only very late in the stationary phase. Gph1p and Sga1p may therefore degrade physically distinct pools of glycogen. Pho85p is a cyclin-dependent protein kinase that antagonizes SNF1control of glycogen synthesis. Induction of autophagy inpho85 mutants entering the stationary phase was exaggerated compared to the level in wild-type cells, but was blocked in apg1 pho85 mutants. We propose that Snf1p and Pho85p are, respectively, positive and negative regulators of autophagy, probably via Apg1 and/or Apg13. Defective glycogen storage in snf1cells can be attributed to both defective synthesis upon entry into stationary phase and impaired maintenance of glycogen levels caused by the lack of autophagy.

scholarly journals Transgenic overexpression of protein targeting to glycogen markedly increases adipocytic glycogen storage in mice

2007 ◽  
Vol 292 (3) ◽  
pp. E952-E963 ◽  
Author(s):  
Michael J. Jurczak ◽  
Arpad M. Danos ◽  
Victoria R. Rehrmann ◽  
Margaret B. Allison ◽  
Cynthia C. Greenberg ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Transgenic Animals ◽  
Glycogen Metabolism ◽  
Glycogen Storage ◽  
Fatty Acid Binding ◽  
Fat Depots

Adipocytes express the rate-limiting enzymes required for glycogen metabolism and increase glycogen synthesis in response to insulin. However, the physiological function of adipocytic glycogen in vivo is unclear, due in part to the low absolute levels and the apparent biophysical constraints of adipocyte morphology on glycogen accumulation. To further study the regulation of glycogen metabolism in adipose tissue, transgenic mice were generated that overexpressed the protein phosphatase-1 (PP1) glycogen-targeting subunit (PTG) driven by the adipocyte fatty acid binding protein (aP2) promoter. Exogenous PTG was detected in gonadal, perirenal, and brown fat depots, but it was not detected in any other tissue examined. PTG overexpression resulted in a modest redistribution of PP1 to glycogen particles, corresponding to a threefold increase in the glycogen synthase activity ratio. Glycogen synthase protein levels were also increased twofold, resulting in a combined greater than sixfold enhancement of basal glycogen synthase specific activity. Adipocytic glycogen levels were increased 200- to 400-fold in transgenic animals, and this increase was maintained to 1 yr of age. In contrast, lipid metabolism in transgenic adipose tissue was not significantly altered, as assessed by lipogenic rates, weight gain on normal or high-fat diets, or circulating free fatty acid levels after a fast. However, circulating and adipocytic leptin levels were doubled in transgenic animals, whereas adiponectin expression was unchanged. Cumulatively, these data indicate that murine adipocytes are capable of storing far higher levels of glycogen than previously reported. Furthermore, these results were obtained by overexpression of an endogenous adipocytic protein, suggesting that mechanisms may exist in vivo to maintain adipocytic glycogen storage at a physiological set point.

scholarly journals Adiponectin regulates glycogen metabolism at the human fetal–maternal interface

2018 ◽  
Vol 61 (3) ◽  
pp. 139-152 ◽  
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.

scholarly journals The effect of streptozotocin-induced diabetes and of insulin supplementation on glycogen metabolism in rat liver

1977 ◽  
Vol 168 (3) ◽  
pp. 541-548 ◽  
Author(s):  
R L Khandelwal ◽  
S M Zinman ◽  
E J Zebrowski
Keyword(s):  
Phosphatase Activity ◽  
Insulin Treatment ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Diabetic Rats ◽  
Phosphorylase Kinase ◽  
Metabolizing Enzymes ◽  
Heat Stable ◽  
Heat Stable Protein ◽  
Streptozotocin Induced Diabetes

The effects of streptozotocin-induced diabetes and of insulin supplementation to diabetic rats on glycogen-metabolizing enzymes in liver were determined. The results were compared with those from control animals. The activities of glycogenolytic enzymes, i.e. phosphorylase (both a and b), phosphorylase kinase and protein kinase (in the presence or in the absence of cyclic AMP), were significantly decreased in the diabetic animals. The enzyme activities were restored to control values by insulin therapy. Glycogen synthase (I-form) activity, similarly decreased in the diabetic animals, was also restored to control values after the administration of insulin. The increase in glycogen synthase(I-form) activity after insulin treatment was associated with a concomitant increase in phosphoprotein phosphatase activity. The increase in phosphatase activity was due to (i) a change in the activity of the enzyme itself and (ii) a decrease in a heat stable protein inhibitor of the phosphatase activity.

Simulation study of control of hepatic glycogen synthesis by glucose and insulin

1976 ◽  
Vol 231 (5) ◽  
pp. 1608-1619 ◽  
Author(s):  
M El-Refai ◽  
RN Bergman
Keyword(s):  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glucose Production ◽  
Mass Action ◽  
Hepatic Glycogen ◽  
Uridine Diphosphate ◽  
Extracellular Glucose ◽  
Diphosphate Glucose ◽  
Glycogen Deposition ◽  
Predicted Values

The plausibility of various hypotheses concerning the effects of glucow dynamic model of glucose metabolism in the liver. The model consisted of six compartments representing extracellular glucose, and intracellular glucose, glucose 6-phosphate, glucose 1-phosphate, uridine diphosphate glucose, obtained from literature reports, the model predicted values of intermediates which were close to those reported for the liver, sampled from fasting animals. The model predicts that glucose can generate significant glycogen deposition by engendering the inhibition of glucose-6-phosphatase, but not by mass action, glycogen synthase activation, or phosphorylase deactivation. The model predicts that, although insulin can inhibit glucose production by lowering phosphorylase and gluconeogenesis, only an insulin-mediated induction of glucokinase can account for insulin's action to potentiate the effect of glucose alone on glycogen synthesis.

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

2018 ◽  
Vol 315 (5) ◽  
pp. C706-C713 ◽  
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.

Effect of hypercorticism on regulation of skeletal muscle glycogen metabolism by insulin

1992 ◽  
Vol 262 (4) ◽  
pp. E427-E433 ◽  
Author(s):  
L. Coderre ◽  
A. K. Srivastava ◽  
J. L. Chiasson
Keyword(s):  
Muscle Glycogen ◽  
Glycogen Content ◽  
Activity Ratio ◽  
Glycogen Synthase ◽  
Glycogen Synthesis ◽  
Glycogen Metabolism ◽  
Dexamethasone Treatment ◽  
Muscle Glycogen Content ◽  
Glycogen Synthase Activity ◽  
Muscle Glycogen Concentration

The effects of hypercorticism on the regulation of glycogen metabolism by insulin in skeletal muscles was examined by using the hindlimb perfusion technique. Rats were injected daily with either saline or dexamethasone (0.4 mg.kg-1.day-1) for 14 days and were studied in the fed or fasted (24 h) state under saline or insulin (1 mU/ml) treatment. In fed controls, insulin resulted in glycogen synthase activation and in enhanced glycogen synthesis. In dexamethasone-treated animals, basal muscle glycogen concentration remained normal, but glycogen synthase activity ratio was decreased in white and red gastrocnemius and plantaris muscles. Furthermore, insulin failed to activate glycogen synthase and glycogen synthesis. In the controls, fasting was associated with decreased glycogen concentrations and with increased glycogen synthase activity ratio in all four groups of muscles (P less than 0.01). Dexamethasone treatment, however, completely abolished the decrease in muscle glycogen content as well as the augmented glycogen synthase activity ratio associated with fasting. Insulin infusion stimulated glycogen synthesis in fasted controls but not in dexamethasone-treated rats. These data therefore indicate that dexamethasone treatment inhibits the stimulatory effect of insulin on glycogen synthase activity and on glycogen synthesis. Furthermore, hypercorticism suppresses the decrease in muscle glycogen content associated with fasting.

Seasonal, tissue-specific regulation of Akt/protein kinase B and glycogen synthase in hibernators

2004 ◽  
Vol 286 (3) ◽  
pp. R498-R504 ◽  
Author(s):  
Kyle L. Hoehn ◽  
Susan F. Hudachek ◽  
Scott A. Summers ◽  
Gregory L. Florant
Keyword(s):  
Protein Kinase ◽  
Body Mass ◽  
Large Scale ◽  
Glycogen Synthase ◽  
Protein Kinase B ◽  
Glycogen Synthesis ◽  
Mass Gain ◽  
Tissue Specific ◽  
Protein Levels ◽  
Specific Regulation

Yellow-bellied marmots ( Marmota flaviventris) exhibit a circannual cycle of hyperphagia and nutrient storage in the summer followed by hibernation in the winter. This annual cycle of body mass gain and loss is primarily due to large-scale accumulation of lipid in the summer, which is then mobilized and oxidized for energy during winter. The rapid and predictable change in body mass makes these animals ideal for studies investigating the molecular basis for body weight regulation. In the study described herein, we monitored seasonal changes in the protein levels and activity of a central regulator of anabolic metabolism, the serine-threonine kinase Akt-protein kinase B (Akt/PKB), during the months accompanying maximal weight gain and entry into hibernation (June-November). Interestingly, under fasting conditions, Akt/PKB demonstrated a tissue-specific seasonal activation. Specifically, although Akt/PKB levels did not change, the activity of Akt/PKB (isoforms 1/α and 2/β) in white adipose tissue (WAT) increased significantly in July. Moreover, glycogen synthase, which lies downstream of Akt/PKB on a linear pathway linking the enzyme to the stimulation of glycogen synthesis, demonstrated a similar pattern of seasonal activation. By contrast, Akt/PKB activity in skeletal muscle peaked much later (i.e., September). These data suggest the existence of a novel, tissue-specific mechanism regulating Akt/PKB activation during periods of marked anabolism.

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