Loss of glyoxalase 2 alters the glucose metabolism in zebrafish
Christoph Tobias Tabler,
Elisabeth Lodd,
Katrin Bennewitz,
Chiara Simone Middel,
Vanessa Erben,
Hannes Ott,
Tanja Poth,
Thomas Fleming,
Jakob Morgenstern,
Ingrid Hausser,
Carsten Sticht,
Gernot Poschet,
Julia Szendroedi,
Peter Paul Nawroth,
Jens Kroll
Affiliations
Christoph Tobias Tabler
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
Elisabeth Lodd
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
Katrin Bennewitz
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
Chiara Simone Middel
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
Vanessa Erben
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
Hannes Ott
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany
Tanja Poth
CMCP - Center for Model System and Comparative Pathology, Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany
Thomas Fleming
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120, Heidelberg, Germany
Jakob Morgenstern
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120, Heidelberg, Germany
Ingrid Hausser
Institute of Pathology IPH, EM Lab, Heidelberg University Hospital, 69120, Heidelberg, Germany
Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, 69120, Heidelberg, Germany
Julia Szendroedi
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120, Heidelberg, Germany
Peter Paul Nawroth
Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, 69120, Heidelberg, Germany
Jens Kroll
Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, 68167, Mannheim, Germany; Corresponding author. European Center for Angioscience (ECAS) Dept. of Vascular Biology & Tumor Angiogenesis Medical Faculty Mannheim, Heidelberg University, Ludolf‐Krehl‐Str. 13‐17, 68167, Mannheim, Germany.
Glyoxalase 2 is the second enzyme of the glyoxalase system, catalyzing the detoxification of methylglyoxal to d-lactate via SD-Lactoylglutathione. Recent in vitro studies have suggested Glo2 as a regulator of glycolysis, but if Glo2 regulates glucose homeostasis and related organ specific functions in vivo has not yet been evaluated. Therefore, a CRISPR-Cas9 knockout of glo2 in zebrafish was created and analyzed. Consistent with its function in methylglyoxal detoxification, SD-Lactoylglutathione, but not methylglyoxal accumulated in glo2−/− larvae, without altering the glutathione metabolism or affecting longevity. Adult glo2−/− livers displayed a reduced hexose concentration and a reduced postprandial P70–S6 kinase activation, but upstream postprandial AKT phosphorylation remained unchanged. In contrast, glo2−/− skeletal muscle remained metabolically intact, possibly compensating for the dysfunctional liver through increased glucose uptake and glycolytic activity. glo2−/− zebrafish maintained euglycemia and showed no damage of the retinal vasculature, kidney, liver and skeletal muscle. In conclusion, the data identified Glo2 as a regulator of cellular energy metabolism in liver and skeletal muscle, but the redox state and reactive metabolite accumulation were not affected by the loss of Glo2.
