Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure

Emilyn U. Alejandro; Nadejda Bozadjieva; Doga Kumusoglu; Sarah Abdulhamid; Hannah Levine; Leena Haataja; Suryakiran Vadrevu; Leslie S. Satin; Peter Arvan; Ernesto Bernal-Mizrachi

doi:10.1016/j.celrep.2015.11.020

Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure

Emilyn U. Alejandro, Nadejda Bozadjieva, Doga Kumusoglu, Sarah Abdulhamid, Hannah Levine, Leena Haataja, Suryakiran Vadrevu, Leslie S. Satin, Peter Arvan, Ernesto Bernal-Mizrachi

Physiology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

Abstract

Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to "fine-tune" intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β cell mass and function is unclear. Here, we reveal that mice lacking β cell OGT (βOGT-KO) develop diabetes and β cell failure. βOGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of β cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in βOGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of βOGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of β cell mass and function and provide a direct link between O-GlcNAcylation and β cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.

Original language	English (US)
Pages (from-to)	2527-2538
Number of pages	12
Journal	Cell reports
Volume	13
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2015.11.020
State	Published - Dec 22 2015

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health grant RO1 DK084236 and DK073716 (to E.B.-M.), R01 DK48280 (to P.A.), and RO1 DK46409 (to L.S.S.). E.U.A. was supported by a Post-Doctoral Fellowship from The Hartwell Foundation and by a Career Development Award from NIDDK (K01-DK-103823). N.B. was supported by the NIH Cellular and Molecular Biology Training Grant T32GM007315. The authors acknowledge support from the Morphology and Image Analysis Core, Metabolomics Core, and Phenotyping Core from the Michigan Diabetes Research Center (P30 DK020572). We thank Drs. Lynda Elghazi and Corentin Cras-Meneur for contribution in the discussion. We thank Ms. Lauren See for her assistance with islet isolation. We thank Mr. Ronald Mark Ygona for illustrating the graphical abstract.

Publisher Copyright:
© 2015 The Authors.

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title = "Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure",

abstract = "Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to {"}fine-tune{"} intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β cell mass and function is unclear. Here, we reveal that mice lacking β cell OGT (βOGT-KO) develop diabetes and β cell failure. βOGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of β cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in βOGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of βOGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of β cell mass and function and provide a direct link between O-GlcNAcylation and β cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.",

author = "Alejandro, {Emilyn U.} and Nadejda Bozadjieva and Doga Kumusoglu and Sarah Abdulhamid and Hannah Levine and Leena Haataja and Suryakiran Vadrevu and Satin, {Leslie S.} and Peter Arvan and Ernesto Bernal-Mizrachi",

note = "Funding Information: This work was supported by National Institutes of Health grant RO1 DK084236 and DK073716 (to E.B.-M.), R01 DK48280 (to P.A.), and RO1 DK46409 (to L.S.S.). E.U.A. was supported by a Post-Doctoral Fellowship from The Hartwell Foundation and by a Career Development Award from NIDDK (K01-DK-103823). N.B. was supported by the NIH Cellular and Molecular Biology Training Grant T32GM007315. The authors acknowledge support from the Morphology and Image Analysis Core, Metabolomics Core, and Phenotyping Core from the Michigan Diabetes Research Center (P30 DK020572). We thank Drs. Lynda Elghazi and Corentin Cras-Meneur for contribution in the discussion. We thank Ms. Lauren See for her assistance with islet isolation. We thank Mr. Ronald Mark Ygona for illustrating the graphical abstract. Publisher Copyright: {\textcopyright} 2015 The Authors.",

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AU - Alejandro, Emilyn U.

AU - Bozadjieva, Nadejda

AU - Kumusoglu, Doga

AU - Abdulhamid, Sarah

AU - Levine, Hannah

AU - Haataja, Leena

AU - Vadrevu, Suryakiran

AU - Satin, Leslie S.

AU - Arvan, Peter

AU - Bernal-Mizrachi, Ernesto

N1 - Funding Information: This work was supported by National Institutes of Health grant RO1 DK084236 and DK073716 (to E.B.-M.), R01 DK48280 (to P.A.), and RO1 DK46409 (to L.S.S.). E.U.A. was supported by a Post-Doctoral Fellowship from The Hartwell Foundation and by a Career Development Award from NIDDK (K01-DK-103823). N.B. was supported by the NIH Cellular and Molecular Biology Training Grant T32GM007315. The authors acknowledge support from the Morphology and Image Analysis Core, Metabolomics Core, and Phenotyping Core from the Michigan Diabetes Research Center (P30 DK020572). We thank Drs. Lynda Elghazi and Corentin Cras-Meneur for contribution in the discussion. We thank Ms. Lauren See for her assistance with islet isolation. We thank Mr. Ronald Mark Ygona for illustrating the graphical abstract. Publisher Copyright: © 2015 The Authors.

PY - 2015/12/22

Y1 - 2015/12/22

N2 - Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to "fine-tune" intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β cell mass and function is unclear. Here, we reveal that mice lacking β cell OGT (βOGT-KO) develop diabetes and β cell failure. βOGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of β cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in βOGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of βOGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of β cell mass and function and provide a direct link between O-GlcNAcylation and β cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.

AB - Nutrient levels dictate the activity of O-linked N-acetylglucosamine transferase (OGT) to regulate O-GlcNAcylation, a post-translational modification mechanism to "fine-tune" intracellular signaling and metabolic status. However, the requirement of O-GlcNAcylation for maintaining glucose homeostasis by regulating pancreatic β cell mass and function is unclear. Here, we reveal that mice lacking β cell OGT (βOGT-KO) develop diabetes and β cell failure. βOGT-KO mice demonstrated increased ER stress and distended ER architecture, and these changes ultimately caused the loss of β cell mass due to ER-stress-induced apoptosis and decreased proliferation. Akt1/2 signaling was also dampened in βOGT-KO islets. The mechanistic role of these processes was demonstrated by rescuing the phenotype of βOGT-KO mice with concomitant Chop gene deletion or genetic reconstitution of Akt2. These findings identify OGT as a regulator of β cell mass and function and provide a direct link between O-GlcNAcylation and β cell survival by regulation of ER stress responses and modulation of Akt1/2 signaling.

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Disruption of O-linked N-Acetylglucosamine Signaling Induces ER Stress and β Cell Failure

Abstract

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