bims-glecem 2023-01-29 papers

Issue of 2023–01–29
five papers selected by
Dipsikha Biswas, Københavns Universitet

Neuroglia. 2022 Dec;3(4): 144-157

Sex-Dimorphic Glucocorticoid Receptor Regulation of Hypothalamic Primary Astrocyte Glycogen Metabolism: Interaction with Norepinephrine.

Prabhat R Napit, Abdulrahman Alhamyani, Khaggeswar Bheemanapally, Paul W Sylvester, Karen P Briski.

Astrocyte glycogen is a critical metabolic variable that impacts hypothalamic control of glucostasis. Glucocorticoid hormones regulate peripheral glycogen, but their effects on hypothalamic glycogen are not known. A hypothalamic astrocyte primary culture model was used to investigate the premise that glucocorticoids impose sex-dimorphic independent and interactive control of glycogen metabolic enzyme protein expression and glycogen accumulation. The glucocorticoid receptor (GR) agonist dexamethasone (DEX) down-regulated glycogen synthase (GS), glycogen phosphorylase (GP)-brain type (GPbb), and GP-muscle type (GPmm) proteins in glucose-supplied male astrocytes, but enhanced these profiles in female. The catecholamine neurotransmitter norepinephrine (NE) did not alter these proteins, but amplified DEX inhibition of GS and GPbb in male or abolished GR stimulation of GPmm in female. In both sexes, DEX and NE individually increased glycogen content, but DEX attenuated the magnitude of noradrenergic stimulation. Glucoprivation suppressed GS, GPbb, and GPmm in male, but not female astrocytes, and elevated or diminished glycogen in these sexes, respectively. Glucose-deprived astrocytes exhibit GR-dependent induced glycogen accumulation in both sexes, and corresponding loss (male) or attenuation (female) of noradrenergic-dependent glycogen build-up. Current evidence for GR augmentation of hypothalamic astrocyte glycogen content in each sex, yet divergent effects on glycogen enzyme proteins infers that glucocorticoids may elicit opposite adjustments in glycogen turnover in each sex. Results document GR modulation of NE stimulation of glycogen accumulation in the presence (male and female) or absence (female) of glucose. Outcomes provide novel proof that astrocyte energy status influences the magnitude of GR and NE signal effects on glycogen mass.

Keywords: LC-ESI-MS; dexamethasone; glucoprivation; glycogen; glycogen phosphorylase isoform; norepinephrine

DOI: https://doi.org/10.3390/neuroglia3040010

Eur J Appl Physiol. 2023 Jan 23.

The role of exercise and hypoxia on glucose transport and regulation.

J Soo, A Raman, N G Lawler, P S R Goods, L Deldicque, O Girard, T J Fairchild.

Muscle glucose transport activity increases with an acute bout of exercise, a process that is accomplished by the translocation of glucose transporters to the plasma membrane. This process remains intact in the skeletal muscle of individuals with insulin resistance and type 2 diabetes mellitus (T2DM). Exercise training is, therefore, an important cornerstone in the management of individuals with T2DM. However, the acute systemic glucose responses to carbohydrate ingestion are often augmented during the early recovery period from exercise, despite increased glucose uptake into skeletal muscle. Accordingly, the first aim of this review is to summarize the knowledge associated with insulin action and glucose uptake in skeletal muscle and apply these to explain the disparate responses between systemic and localized glucose responses post-exercise. Herein, the importance of muscle glycogen depletion and the key glucoregulatory hormones will be discussed. Glucose uptake can also be stimulated independently by hypoxia; therefore, hypoxic training presents as an emerging method for enhancing the effects of exercise on glucose regulation. Thus, the second aim of this review is to discuss the potential for systemic hypoxia to enhance the effects of exercise on glucose regulation.

Keywords: Exercise; Glucose; Glucose metabolism; Hypoxia; Insulin resistance

DOI: https://doi.org/10.1007/s00421-023-05135-1

JACC Basic Transl Sci. 2022 Nov;7(11): 1102-1116

Novel GSK-3β Inhibitor Neopetroside A Protects Against Murine Myocardial Ischemia/Reperfusion Injury.

Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2-related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.

Keywords: ATP, adenosine triphosphate; GSK-3, glycogen synthase kinase–3; GSK-3β inhibition; I/R, ischemia/reperfusion; MI, myocardial infarction; NAD+, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide, reduced; NPS A; NPS A, neopetroside A; Nqo1, NAD(P)H:quinone oxidoreductase 1; Nrf2, nuclear factor erythroid 2–related factor 2; OCR, oxygen consumption rate; ischemia/reperfusion injury; mPTP, mitochondrial permeability transition pore; mTOR, mammalian target of rapamycin; marine pyridine α-nucleoside; mitochondria

DOI: https://doi.org/10.1016/j.jacbts.2022.05.004

Comput Biol Chem. 2023 Jan 18. pii: S1476-9271(23)00009-9. [Epub ahead of print]103 107818

GlucoKinaseDB: A comprehensive, curated resource of glucokinase modulators for clinical and molecular research.

Siddharth Yadav, Samuel Bharti, Puniti Mathur.

Glucokinase (GK), an isoform of hexokinase expressed predominantly in liver, pancreas and hypothalamus is crucial to blood glucose management. It is a critical component of the glucose-sensing mechanism of the pancreatic islet cells and glycogen regulation in hepatocytes. GK modulators such as allosteric GKAs (glucokinase activators) and GK-GKRP (glucokinase regulatory protein) disruptors have found potential applications as safer antihyperglycemics. Recent studies have also demonstrated the potential of GK modulators as antiparasitic agents. Researchers targeting GK often undertake the time-consuming task of independently collecting and compiling modulator information due to the lack of any dedicated single-platform resource. Towards this, in the present study we demonstrate the design and development of GlucoKinaseDB (GKDB), a comprehensive, curated, online resource of GK modulators. GKDB contains experimentally derived structural and bioactivity information of 1723 modulators along with their detailed molecular descriptors. The web-interface is user-friendly with features such as in-browser visualization, advanced search queries, cross-links to other databases and original reference etc. The bioactivity and descriptor data can be downloaded in bulk (for entire database) or for individual modulators. The 3D structures are also downloadable in multiple formats. GKDB employs a PHP-based web design with Bootstrap styling and a MySQL database backend. GKDB can be utilized for clinical and molecular research via development of pharmacophore hypotheses, QSAR/QSPR models, predictive machine learning models etc. GKDB is freely accessible online at https://glucokinasedb.in.

Keywords: Database; Diabetes; Glucokinase; Glucokinase modulators; Pharmacophore development; Web resource

DOI: https://doi.org/10.1016/j.compbiolchem.2023.107818

Life Sci Space Res (Amst). 2023 Feb;pii: S2214-5524(22)00099-2. [Epub ahead of print]36 18-26

Glycogen metabolism is required for optimal cyanobacterial growth in the rapid light-dark cycle of low-Earth orbit.

Bryan Bishé, Susan S Golden, James W Golden.

Some designs for bioregenerative life support systems to enable human space missions incorporate cyanobacteria for removal of carbon dioxide, generation of oxygen, and treatment of wastewater, as well as providing a source of nutrition. In this study, we examined the effects of the short light-dark (LD) cycle of low-Earth orbit on algal and cyanobacterial growth, approximating conditions on the International Space Station, which orbits Earth roughly every 90 min. We found that growth of green algae was similar in both normal 12 h light:12 h dark (12 h:12 h LD) and 45':45' LD cycles. Three diverse strains of cyanobacteria were not only capable of growth in short 45':45' LD cycles, but actually grew better than in 12 h:12 h LD cycles. We showed that 45':45' LD cycles do not affect the endogenous 24 h circadian rhythms of Synechococcus elongatus. Using a dense library of randomly barcoded transposon mutants, we identified genes whose loss is detrimental for the growth of S. elongatus under 45':45' LD cycles. These include several genes involved in glycogen metabolism and the oxidative pentose phosphate pathway. Notably, 45':45' LD cycles did not affect the fitness of strains that carry mutations in the biological circadian oscillator or the clock input and output regulatory pathways. Overall, this study shows that cultures of cyanobacteria could be grown under natural sunlight of low-Earth orbit and highlights the utility of a functional genomic study in a model organism to better understand key biological processes in conditions that are relevant to space travel.

Keywords: Bioregenerative life support; Circadian rhythms; Cyanobacteria; Low-Earth orbit

DOI: https://doi.org/10.1016/j.lssr.2022.11.001