The human batokine EPDR1 regulates β-cell metabolism and function
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The human batokine EPDR1 regulates β-cell metabolism and function. / Cataldo, Luis Rodrigo; Gao, Qian; Argemi-Muntadas, Lidia; Hodek, Ondrej; Cowan, Elaine; Hladkou, Sergey; Gheibi, Sevda; Spegel, Peter; Prasad, Rashmi B.; Eliasson, Lena; Scheele, Camilla; Fex, Malin; Mulder, Hindrik; Moritz, Thomas.
In: Molecular Metabolism, Vol. 66, 101629, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The human batokine EPDR1 regulates β-cell metabolism and function
AU - Cataldo, Luis Rodrigo
AU - Gao, Qian
AU - Argemi-Muntadas, Lidia
AU - Hodek, Ondrej
AU - Cowan, Elaine
AU - Hladkou, Sergey
AU - Gheibi, Sevda
AU - Spegel, Peter
AU - Prasad, Rashmi B.
AU - Eliasson, Lena
AU - Scheele, Camilla
AU - Fex, Malin
AU - Mulder, Hindrik
AU - Moritz, Thomas
PY - 2022
Y1 - 2022
N2 - Objective: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic 0-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in 0-cells, the role of EPDR1 in 0-cell metabolism and function has not been investigated.Methods: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-0H1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis.Results: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and 0-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose-and pyruvate-but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells.Conclusion: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve 0-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
AB - Objective: Ependymin-Related Protein 1 (EPDR1) was recently identified as a secreted human batokine regulating mitochondrial respiration linked to thermogenesis in brown fat. Despite that EPDR1 is expressed in human pancreatic 0-cells and that glucose-stimulated mitochondrial metabolism is critical for stimulus-secretion coupling in 0-cells, the role of EPDR1 in 0-cell metabolism and function has not been investigated.Methods: EPDR1 mRNA levels in human pancreatic islets from non-diabetic (ND) and type 2 diabetes (T2D) subjects were assessed. Human islets, EndoC-0H1 and INS1 832/13 cells were transfected with scramble (control) and EPDR1 siRNAs (EPDR1-KD) or treated with human EPDR1 protein, and glucose-stimulated insulin secretion (GSIS) assessed by ELISA. Mitochondrial metabolism was investigated by extracellular flux analyzer, confocal microscopy and mass spectrometry-based metabolomics analysis.Results: EPDR1 mRNA expression was upregulated in human islets from T2D and obese donors and positively correlated to BMI of donors. In T2D donors, EPDR1 mRNA levels negatively correlated with HbA1c and positively correlated with GSIS. EPDR1 silencing in human islets and 0-cell lines reduced GSIS whereas treatment with human EPDR1 protein increased GSIS. Epdr1 silencing in INS1 832/13 cells reduced glucose-and pyruvate-but not K+-stimulated insulin secretion. Metabolomics analysis in Epdr1-KD INS1 832/13 cells suggests diversion of glucose-derived pyruvate to lactate production and decreased malate-aspartate shuttle and the tricarboxylic acid (TCA) cycle activity. The glucose-stimulated rise in mitochondrial respiration and ATP/ADP-ratio was impaired in Epdr1-deficient cells.Conclusion: These results suggests that to maintain glucose homeostasis in obese people, upregulation of EPDR1 may improve 0-cell function via channelling glycolysis-derived pyruvate to the mitochondrial TCA cycle.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
KW - Mitochondrial metabolism
KW - Lactate
KW - TCA cycle
KW - Beta cells
KW - Insulin secretion
KW - Type 2 diabetes
KW - GENOME-WIDE ASSOCIATION
KW - BETA-CELL
KW - INSULIN-SECRETION
KW - MITOCHONDRIAL METABOLISM
KW - GLUCOSE-METABOLISM
KW - EXPRESSION
KW - IDENTIFICATION
KW - GENES
KW - REVEAL
KW - PATHWAYS
U2 - 10.1016/j.molmet.2022.101629
DO - 10.1016/j.molmet.2022.101629
M3 - Journal article
C2 - 36343918
VL - 66
JO - Molecular Metabolism
JF - Molecular Metabolism
SN - 2212-8778
M1 - 101629
ER -
ID: 337595526