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Glycogen synthase 2 knock-out zebrafish exhibit enhanced glucose metabolism in the liver

ABSTRACT: The liver is one of the major organs for glycogen storage and is essential for maintaining glucose homeostasis in the whole body. Glycogen synthesis in liver is regulated by the rate-limiting enzyme, glycogen synthase 2 (Gys2). In fish, however, the detailed roles of glycogen and Gys2 is poorly understood. In this study, we generated, for the first time, gys2 knock-out (gys2 -/-) zebrafish and evaluated the effects of impaired glycogen synthesis on physiological parameters of this fish. No effects on development or maturation were observed in gys2 -/- strain lacking Gys2. PAS staining, immunofluorescence staining with anti-glycogen antibody, and transmission electron microscopy (TEM) observations confirmed that glycogen synthesis does not occur in the gys2 -/- liver. However, glucoamylase treatment released higher amount of glucose from gys2 -/- liver extract than that of the wild-type (WT) counterpart, suggesting the existence of putative compensatory glucose polymer in the gys2 -/- liver. Liquid chromatography-mass spectrometry (LC-MS/MS) metabolite analysis and isotope tracing revealed a marked increase in the activity of glucose metabolism and levels of related metabolites in the livers of adult gys2 -/-. However, RNA-Seq analysis showed no corresponding changes in the expression levels of glucose metabolism–related genes. These results suggest that liver Gys2 is dispensable in zebrafish, and enhanced glucose metabolism and putative backup mechanism to accumulate extra glucose may support the fish lacking Gys2.

ORGANISM(S): Danio rerio

PROVIDER: GSE311007 | GEO | 2025/12/19

REPOSITORIES: GEO

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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.

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Glycogen synthase 2 knock-out zebrafish exhibit enhanced glucose metabolism in the liver

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