Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31637354_1.fastq.gz | Fastqsanger.gz | |||
| SRR31637354_2.fastq.gz | Fastqsanger.gz | |||
| SRR31637355_1.fastq.gz | Fastqsanger.gz | |||
| SRR31637355_2.fastq.gz | Fastqsanger.gz | |||
| SRR31637356_1.fastq.gz | Fastqsanger.gz |
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Project description:Nrf2 (NF-E2-related-factor-2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic β-cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1-knockout (Keap1MuKO) mice that express abundant Nrf2 in SkM and then examined Nrf2-target gene expression in this tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated, and the levels of glycogen branching enzyme (Gbe1) mRNA, along with those of glycogen branching enzyme (GBE) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2-inducers promoted Gbe1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin-immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced, and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2-induction in SkM increases GBE expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Chromatin occupancy of Nrf2 under CDDO-Im-treated condition were generated by deep sequencing, in dupliplicate
2016-04-06 | E-GEOD-78780 | biostudies-arrayexpress
Project description:The glycogen scaffolding protein PTG coordinately regulates glycogen and lipid storage
| PRJNA193449 | ENA
Project description:Exercise-induced fatigue and exhaustion have been an interesting area for many physiologists.Muscle glycogen is critical forphysical performance. However, how glycogen depletion is manipulated during exercise is not very clear. Our aim here is to assess the impact of interferon regulatory factor 4 (IRF4) on skeletal muscle glycogen and subsequent regulation ofexercise capacity. Skeletal muscle-specific IRF4 knockout mice show normal body weight and insulin sensitivity, but better exercise capacity and increased glycogen content with unaltered triglyceride levels compared to control mice on chow diet. In contrast, mice overexpression of IRF4 display decreased exercise capacity and lower glycogen content. Mechanistically, IRF4 regulates glycogen-associated regulatory subunit protein targeting to glycogen (PTG) to manipulate glucose metabolism. Knockdown of PTG can reverse the effects imposed by the absence of IRF4in vivo. Our studies reveal a regulatory pathway including IRF4/PTG/glycogen synthesis that controlling exercise capacity.
2019-11-19 | GSE140633 | GEO
Project description:Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown. Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of 13C-glucose. Cardiac glycogen was measured biochemically and by transmission electron microscopy. Cardiac glucose uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the heart failure in CS-Mpc2-/- mice. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed either low-fat or ketogenic diet. Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, suggesting their heart failure is not caused by energetic stress. These hearts displayed increased enrichment from 13C-glucose and increased glycolytic metabolite pool sizes. 13C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ~6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of the priming enzyme glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet. Conclusions: Our results indicate that loss of MPC in the heart increases glycolytic metabolism and ultimately glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is dramatically reduced by consumption of a ketogenic diet.
2024-06-03 | GSE268694 | GEO
Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
2021-10-06 | GSE148933 | GEO
Project description:Nrf2 (NF-E2-related-factor-2) contributes to the maintenance of glucose homeostasis in vivo. Nrf2 suppresses blood glucose levels by protecting pancreatic β-cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1-knockout (Keap1MuKO) mice that express abundant Nrf2 in SkM and then examined Nrf2-target gene expression in this tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated, and the levels of glycogen branching enzyme (Gbe1) mRNA, along with those of glycogen branching enzyme (GBE) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2-inducers promoted Gbe1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin-immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced, and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2-induction in SkM increases GBE expression and reduces muscle glycogen content, resulting in improved glucose tolerance.
2016-04-06 | GSE78780 | GEO
Project description:In this study, we aimed at uncovering the molecular mechanisms underlying POMC neuron sensory activation and the mediated behavioral and metabolic processes. Unexpectedly, we found that glycogen metabolism is rapidly engaged in POMC neurons upon sensory food perception. Genetic deletion of glycogen synthase, the sole enzyme able to make glycogen in vivo, in POMC neurons impedes food-related sensory activation while causing impairments in food awareness, short-term food intake and insulin release. These perturbations associate with whole-body metabolic defects, including overweight and insulin resistance, that are exacerbated by high-dense diets or ageing. Collectively, our study identifies glycogen metabolism as an unanticipated mechanistic driver of POMC neuron sensory activation and provides paradigm-shift evidences of the importance of neuronal glycogen for physiology.
2024-01-31 | GSE224274 | GEO
Project description:Ischemic stroke induces pathological glycogen deposition in astrocytes, but its role in post-injury neural dysfunction remains undefined. We reveal that glycogen-laden astrocytes in the ischemic penumbra undergo HDAC3-dependent mitochondrial fragmentation via a stress granule-mediated mechanism, exacerbating neuronal injury and hindering functional recovery. Mechanistic studies demonstrate that glycogen aggregates sequester cytoplasmic HDAC3, enabling its translocation to mitochondria. There, HDAC3 deacetylates outer mitochondrial membrane protein ATAD3A, promoting oligomerization-driven mitochondrial fission. Astrocyte-specific ATAD3A ablation prevents stroke-induced synaptic disorganization, neural circuit disruption, and cognitive deficits. Therapeutically, combined administration of cotadutide (a glycogen-depleting GLP-1/GCGR agonist) and HDAC3 inhibitor RGFP966 reverses glycogen accumulation, rescues mitochondrial architecture/function, and restores synaptic plasticity and circuit reorganization, thereby accelerating sensorimotor recovery. Our work identifies glycogen stress granules as pathogenic signaling hubs linking astrocytic metabolic stress to mitochondrial failure through compartmentalized HDAC3-ATAD3A crosstalk, and proposes a dual-target paradigm addressing both substrate overload and protein acetylation dynamics for stroke neurorestoration.
2025-05-10 | GSE295882 | GEO
Project description:Glycogen storage, conversion and utilization in astrocytes play important roles in brain energy metabolism. The conversion of glycogen to lactate through glycolysis occurs through the coordinated activities of various enzymes, and inhibition of this process can impair different brain processes including formation of long-lasting memories. To replenish depleted glycogen stores, astrocytes undergo glycogen synthesis, a cellular process that has been shown to require transcription and translation during specific stimulation paradigms. However, the detailed nuclear signaling mechanisms and transcriptional regulation during glycogen synthesis in astrocytes remain to be explored. In this report, we study the molecular details of vasoactive intestinal peptide (VIP)-induced glycogen synthesis in astrocytes. VIP is a potent neuropeptide that triggers glycogenolysis followed by glycogen synthesis in astrocytes. We show evidence that VIP-induced glycogen synthesis requires CREB-mediated transcription that is Protein Kinase C and calcium-dependent but is independent of Protein Kinase A. In parallel to CREB activation, we demonstrate that VIP also triggers nuclear accumulation of the CREB coactivator CRTC2 only in astrocytic nuclei that also requires Protein Kinase C activity. Transcriptome profiles of VIP-induced astrocytes identified robust CREB-dependent transcription of glycogenic genes including the upregulation of Ppp1r3c along with robust repression of Phkg1, the catalytic subunit of phosphorylase kinase. Overall, our data demonstrates the importance of CREB-mediated transcription in astrocytes during stimulus-driven glycogenesis.
2024-04-30 | GSE243500 | GEO
Project description:A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in the prior exercised muscle. The molecular mechanisms underlying this well-known phenomenon remain elusive. Here we report that a single bout of exercise induces marked activation of glycogen synthase (GS) and AMP-activated protein kinase (AMPK) for several days beyond normalized muscle glycogen content in man. Acute muscle specific deletion of AMPK activity in mouse muscle abrogated the ability for glycogen supercompensation, providing genetic evidence that AMPK serves as essential driver for glycogen supercompensation. Muscle proteomic analyses revealed elevated glucose uptake capacity in the prior exercised muscle while key proteins in fat oxidation and glycolysis largely remained unchanged. The temporal order of these sustained cellular alterations induced by a single bout of exercise provide a mechanism to offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen, ultimately leading to muscle glycogen supercompensation.
2018-08-30 | PXD009196 | Pride