Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo
Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OG...
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| Format: | Article |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2022.1040014/full |
| _version_ | 1811234845529997312 |
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| author | Seokwon Jo Samantha Pritchard Alicia Wong Alicia Wong Nandini Avula Ahmad Essawy John Hanover Emilyn U. Alejandro |
| author_facet | Seokwon Jo Samantha Pritchard Alicia Wong Alicia Wong Nandini Avula Ahmad Essawy John Hanover Emilyn U. Alejandro |
| author_sort | Seokwon Jo |
| collection | DOAJ |
| description | Protein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demonstrated that hypo-O-GlcNAcylation in β-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and β-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from β-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive β-cell OGA ablation (βOGAKO) to specifically increase O-GlcNAcylation in β-cells. Under normal chow diet, young male and female βOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in β-cell mass was observed between βOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in βOGAKO islets. βOGAKO mice showed deficit in insulin secretion in vivo and in vitro. When young animals were subjected to HFD, both male and female βOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable β-cell mass was found between βOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in β-cells reduces β-cell function, thereby perturbing glucose homeostasis. The findings reinforce the rheostat model of intracellular O-GlcNAcylation where too much (OGA loss) or too little (OGT loss) O-GlcNAcylation are both detrimental to the β-cell. |
| first_indexed | 2024-04-12T11:43:12Z |
| format | Article |
| id | doaj.art-c526a5a84dea408e9ce3e1b64026f57d |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-12T11:43:12Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-c526a5a84dea408e9ce3e1b64026f57d2022-12-22T03:34:32ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922022-10-011310.3389/fendo.2022.10400141040014Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivoSeokwon Jo0Samantha Pritchard1Alicia Wong2Alicia Wong3Nandini Avula4Ahmad Essawy5John Hanover6Emilyn U. Alejandro7Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United StatesDepartment of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United StatesDepartment of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United StatesDepartment of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN, United StatesDepartment of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United StatesDepartment of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United StatesLaboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, United StatesDepartment of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, MN, United StatesProtein O-GlcNAcylation is a nutrient and stress-sensitive protein post-translational modification (PTM). The addition of an O-GlcNAc molecule to proteins is catalyzed by O-GlcNAc transferase (OGT), whereas O-GlcNAcase (OGA) enzyme is responsible for removal of this PTM. Previous work showed that OGT is highly expressed in the pancreas, and we demonstrated that hypo-O-GlcNAcylation in β-cells cause severe diabetes in mice. These studies show a direct link between nutrient-sensitive OGT and β-cell health and function. In the current study, we hypothesized that hyper-O-GlcNAcylation may confer protection from β-cell failure in high-fat diet (HFD)-induced obesity. To test this hypothesis, we generated a mouse model with constitutive β-cell OGA ablation (βOGAKO) to specifically increase O-GlcNAcylation in β-cells. Under normal chow diet, young male and female βOGAKO mice exhibited normal glucose tolerance but developed glucose intolerance with aging, relative to littermate controls. No alteration in β-cell mass was observed between βOGAKO and littermate controls. Total insulin content was reduced despite an increase in pro-insulin to insulin ratio in βOGAKO islets. βOGAKO mice showed deficit in insulin secretion in vivo and in vitro. When young animals were subjected to HFD, both male and female βOGAKO mice displayed normal body weight gain and insulin tolerance but developed glucose intolerance that worsened with longer exposure to HFD. Comparable β-cell mass was found between βOGAKO and littermate controls. Taken together, these data demonstrate that the loss of OGA in β-cells reduces β-cell function, thereby perturbing glucose homeostasis. The findings reinforce the rheostat model of intracellular O-GlcNAcylation where too much (OGA loss) or too little (OGT loss) O-GlcNAcylation are both detrimental to the β-cell.https://www.frontiersin.org/articles/10.3389/fendo.2022.1040014/fullO‐linked N‐acetylglucosamine (O‐GlcNAc)O-GlcNAcylationO-GlcNAcase (OGA)beta cell (β‐cell)insulininsulin secretion |
| spellingShingle | Seokwon Jo Samantha Pritchard Alicia Wong Alicia Wong Nandini Avula Ahmad Essawy John Hanover Emilyn U. Alejandro Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo Frontiers in Endocrinology O‐linked N‐acetylglucosamine (O‐GlcNAc) O-GlcNAcylation O-GlcNAcase (OGA) beta cell (β‐cell) insulin insulin secretion |
| title | Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo |
| title_full | Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo |
| title_fullStr | Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo |
| title_full_unstemmed | Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo |
| title_short | Pancreatic β-cell hyper-O-GlcNAcylation leads to impaired glucose homeostasis in vivo |
| title_sort | pancreatic β cell hyper o glcnacylation leads to impaired glucose homeostasis in vivo |
| topic | O‐linked N‐acetylglucosamine (O‐GlcNAc) O-GlcNAcylation O-GlcNAcase (OGA) beta cell (β‐cell) insulin insulin secretion |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2022.1040014/full |
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