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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MDPI AG
2021-10-01
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| author | Ramkumar Mohan Seokwon Jo Elina Da Sol Chung Eunice Oribamise Amber Lockridge Juan E. Abrahante-Lloréns Hai-Bin Ruan Xiao-Yong Yang Emilyn U. Alejandro |
| author_facet | Ramkumar Mohan Seokwon Jo Elina Da Sol Chung Eunice Oribamise Amber Lockridge Juan E. Abrahante-Lloréns Hai-Bin Ruan Xiao-Yong Yang Emilyn U. Alejandro |
| author_sort | Ramkumar Mohan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:39:41Z |
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| id | doaj.art-96bd25cb755c4432b74adb896f3ea59e |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T06:39:41Z |
| publishDate | 2021-10-01 |
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| series | Cells |
| spelling | doaj.art-96bd25cb755c4432b74adb896f3ea59e2023-11-22T17:49:23ZengMDPI AGCells2073-44092021-10-011010280110.3390/cells10102801Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female MiceRamkumar Mohan0Seokwon Jo1Elina Da Sol Chung2Eunice Oribamise3Amber Lockridge4Juan E. Abrahante-Lloréns5Hai-Bin Ruan6Xiao-Yong Yang7Emilyn U. Alejandro8Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USADepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USASupercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USADepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USAProgram in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University, New Haven, CT 06520, USADepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USAThe 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.https://www.mdpi.com/2073-4409/10/10/2801O-GlcNAc transferaseisletstreptozocin |
| spellingShingle | Ramkumar Mohan Seokwon Jo Elina Da Sol Chung Eunice Oribamise Amber Lockridge Juan E. Abrahante-Lloréns Hai-Bin Ruan Xiao-Yong Yang Emilyn U. Alejandro Pancreatic β-Cell O-GlcNAc Transferase Overexpression Increases Susceptibility to Metabolic Stressors in Female Mice Cells O-GlcNAc transferase islet streptozocin |
| 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 | O-GlcNAc transferase islet streptozocin |
| url | https://www.mdpi.com/2073-4409/10/10/2801 |
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