Loss of the glucocorticoid receptor in zebrafish improves muscle glucose availability and increases growth

Faught, E., Vijayan, M.M.
American journal of physiology. Endocrinology and metabolism   316(6): E1093-E1104 (Journal)
Registered Authors
Faught, Erin, Vijayan, Mathilakath
CRISPR/Cas9, Fish, Glucocorticoid receptor, Intermediary metabolism, Stress
MeSH Terms
  • Animals
  • Body Weight
  • Eukaryotic Initiation Factors
  • Gene Knockout Techniques
  • Gluconeogenesis
  • Glucose/metabolism*
  • HSP70 Heat-Shock Proteins/metabolism
  • Hexokinase/metabolism
  • Hydrocortisone/metabolism*
  • Lipid Metabolism
  • Liver/metabolism*
  • Metabolomics
  • Muscle, Skeletal/growth & development
  • Muscle, Skeletal/metabolism*
  • Protein Biosynthesis
  • Receptors, Glucocorticoid/genetics*
  • Stress, Physiological*
  • Zebrafish
30939052 Full text @ Am. J. Physiol. Endocrinol. Metab.
Chronic stress and the associated elevation in corticosteroid levels increase muscle protein catabolism. We hypothesized that the GR-regulated restriction of muscle glucose availability may play a role in the increased protein catabolism during chronic stress. To test this, we generated a ubiquitous GR knockout (GRKO) zebrafish to determine the physiological consequence of glucocorticoid stimulation on muscle metabolism and growth. Adult GRKO zebrafish had higher body mass, and this corresponded with an increased protein and lipid, but not carbohydrate content. GRKO fish were hypercortisolemic, but they elicited a higher cortisol response to an acute stressor. However, the stressor-induced increase in plasma glucose level observed in the wildtype was completely abolished in the GRKO fish. Also, the muscle, but not liver, capacity for glucose uptake was enhanced in the GRKO fish, and this corresponded with a higher hexokinase activity in the mutants. Zebrafish lacking GR also showed a higher capacity for protein synthesis, including increased phosphorylation of eIF4B, higher expression of heat shock protein cognate 70, and total protein content. A chronic fasting stressor reduced body mass and muscle protein content in adult zebrafish, but this decrease was attenuated in the GRKO compared to the wildtype fish. Metabolomics analysis revealed that the free pool of amino acid substrates used for oxidation and gluconeogenesis were lower in the fasted GRKO fish muscle compared to the wildtype. Altogether, chronic stressor-mediated GR signalling limits muscle glucose uptake, and this may play a role in protein catabolism, leading to the growth suppression in fish.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes