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Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice

The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to meta...

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Autores principales: Mohan, Ramkumar, Jo, Seokwon, Da Sol Chung, Elina, Oribamise, Eunice, Lockridge, Amber, Abrahante-Lloréns, Juan E., Ruan, Hai-Bin, Yang, Xiao-Yong, Alejandro, Emilyn U.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534823/
https://www.ncbi.nlm.nih.gov/pubmed/34685781
http://dx.doi.org/10.3390/cells10102801
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author Mohan, Ramkumar
Jo, Seokwon
Da Sol Chung, Elina
Oribamise, Eunice
Lockridge, Amber
Abrahante-Lloréns, Juan E.
Ruan, Hai-Bin
Yang, Xiao-Yong
Alejandro, Emilyn U.
author_facet Mohan, Ramkumar
Jo, Seokwon
Da Sol Chung, Elina
Oribamise, Eunice
Lockridge, Amber
Abrahante-Lloréns, Juan E.
Ruan, Hai-Bin
Yang, Xiao-Yong
Alejandro, Emilyn U.
author_sort Mohan, Ramkumar
collection PubMed
description The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a β-cell-specific Ogt in overexpressing (βOgtOE) mice, where a significant increase in Ogt protein level and O-GlcNAc-modification of proteins were observed in islets under a normal chow diet. We uncovered that βOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female βOgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal β-cell mass. While female mice are normally resistant to low-dose STZ treatments, the βOgtOE Hz mice developed hyperglycemia and glucose intolerance post-STZ treatment. Transcriptome analysis between islets with loss or gain of Ogt by RNA sequencing shows common altered pathways involving pro-survival Erk and Akt and inflammatory regulators IL1β and NFkβ. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in β-cell survival and function to regulate glucose homeostasis.
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spelling pubmed-85348232021-10-23 Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice Mohan, Ramkumar Jo, Seokwon Da Sol Chung, Elina Oribamise, Eunice Lockridge, Amber Abrahante-Lloréns, Juan E. Ruan, Hai-Bin Yang, Xiao-Yong Alejandro, Emilyn U. Cells Article The nutrient-sensor O-GlcNAc transferase (Ogt), the sole enzyme that adds an O-GlcNAc-modification onto proteins, plays a critical role for pancreatic β-cell survival and insulin secretion. We hypothesized that β-cell Ogt overexpression would confer protection from β-cell failure in response to metabolic stressors, such as high-fat diet (HFD) and streptozocin (STZ). Here, we generated a β-cell-specific Ogt in overexpressing (βOgtOE) mice, where a significant increase in Ogt protein level and O-GlcNAc-modification of proteins were observed in islets under a normal chow diet. We uncovered that βOgtOE mice show normal peripheral insulin sensitivity and glucose tolerance with a regular chow diet. However, when challenged with an HFD, only female βOgtOE (homozygous) Hz mice developed a mild glucose intolerance, despite increased insulin secretion and normal β-cell mass. While female mice are normally resistant to low-dose STZ treatments, the βOgtOE Hz mice developed hyperglycemia and glucose intolerance post-STZ treatment. Transcriptome analysis between islets with loss or gain of Ogt by RNA sequencing shows common altered pathways involving pro-survival Erk and Akt and inflammatory regulators IL1β and NFkβ. Together, these data show a possible gene dosage effect of Ogt and the importance O-GlcNAc cycling in β-cell survival and function to regulate glucose homeostasis. MDPI 2021-10-19 /pmc/articles/PMC8534823/ /pubmed/34685781 http://dx.doi.org/10.3390/cells10102801 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mohan, Ramkumar
Jo, Seokwon
Da Sol Chung, Elina
Oribamise, Eunice
Lockridge, Amber
Abrahante-Lloréns, Juan E.
Ruan, Hai-Bin
Yang, Xiao-Yong
Alejandro, Emilyn U.
Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice
title Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice
title_full Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice
title_fullStr Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice
title_full_unstemmed Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice
title_short Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice
title_sort pancreatic β-cell o-glcnac transferase overexpression increases susceptibility to metabolic stressors in female mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534823/
https://www.ncbi.nlm.nih.gov/pubmed/34685781
http://dx.doi.org/10.3390/cells10102801
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