The human batokine EPDR1 regulates β-cell metabolism and function

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

Harvard

Cataldo, LR, Gao, Q, Argemi-Muntadas, L, Hodek, O, Cowan, E, Hladkou, S, Gheibi, S, Spegel, P, Prasad, RB, Eliasson, L, Scheele, C, Fex, M, Mulder, H & Moritz, T 2022, 'The human batokine EPDR1 regulates β-cell metabolism and function', Molecular Metabolism, vol. 66, 101629. https://doi.org/10.1016/j.molmet.2022.101629

APA

Cataldo, L. R., Gao, Q., Argemi-Muntadas, L., Hodek, O., Cowan, E., Hladkou, S., Gheibi, S., Spegel, P., Prasad, R. B., Eliasson, L., Scheele, C., Fex, M., Mulder, H., & Moritz, T. (2022). The human batokine EPDR1 regulates β-cell metabolism and function. Molecular Metabolism, 66, [101629]. https://doi.org/10.1016/j.molmet.2022.101629

Vancouver

Cataldo LR, Gao Q, Argemi-Muntadas L, Hodek O, Cowan E, Hladkou S et al. The human batokine EPDR1 regulates β-cell metabolism and function. Molecular Metabolism. 2022;66. 101629. https://doi.org/10.1016/j.molmet.2022.101629

Author

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. / The human batokine EPDR1 regulates β-cell metabolism and function. In: Molecular Metabolism. 2022 ; Vol. 66.

Bibtex

@article{dc28f6e366484589957471e64a3fabd4,
title = "The human batokine EPDR1 regulates β-cell metabolism and function",
abstract = "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/).",
keywords = "Mitochondrial metabolism, Lactate, TCA cycle, Beta cells, Insulin secretion, Type 2 diabetes, GENOME-WIDE ASSOCIATION, BETA-CELL, INSULIN-SECRETION, MITOCHONDRIAL METABOLISM, GLUCOSE-METABOLISM, EXPRESSION, IDENTIFICATION, GENES, REVEAL, PATHWAYS",
author = "Cataldo, {Luis Rodrigo} and Qian Gao and Lidia Argemi-Muntadas and Ondrej Hodek and Elaine Cowan and Sergey Hladkou and Sevda Gheibi and Peter Spegel and Prasad, {Rashmi B.} and Lena Eliasson and Camilla Scheele and Malin Fex and Hindrik Mulder and Thomas Moritz",
year = "2022",
doi = "10.1016/j.molmet.2022.101629",
language = "English",
volume = "66",
journal = "Molecular Metabolism",
issn = "2212-8778",
publisher = "Elsevier",

}

RIS

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