SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression
Abstract Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resis...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2015-11-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/ncomms9917 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850207371183259648 |
|---|---|
| author | Lan Shao Huanjiao Jenny Zhou Haifeng Zhang Lingfeng Qin John Hwa Zhong Yun Weidong Ji Wang Min |
| author_facet | Lan Shao Huanjiao Jenny Zhou Haifeng Zhang Lingfeng Qin John Hwa Zhong Yun Weidong Ji Wang Min |
| author_sort | Lan Shao |
| collection | DOAJ |
| description | Abstract Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri-pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-κB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-κB essential molecule, NEMO, at lysine 277/309, leading to increased NF-κB activity, cytokine production and pancreatic inflammation. We further show that NF-κB inhibitors could inhibit pre-diabetic cytokine production, β-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-κB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction. |
| format | Article |
| id | doaj-art-62eedb345534400a9d8a98a531a341f2 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2015-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-62eedb345534400a9d8a98a531a341f22025-08-20T02:10:32ZengNature PortfolioNature Communications2041-17232015-11-016112010.1038/ncomms9917SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progressionLan Shao0Huanjiao Jenny Zhou1Haifeng Zhang2Lingfeng Qin3John Hwa4Zhong Yun5Weidong Ji6Wang Min7The First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen UniversityDepartment of Pathology, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of MedicineDepartment of Pathology, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of MedicineDepartment of Pathology, Interdepartmental Program in Vascular Biology and Therapeutics, Yale University School of MedicineDepartment of Internal Medicine and Section of Cardiology, Yale University School of MedicineDepartment of Therapeutic Radiology, Yale University School of MedicineThe First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen UniversityThe First Affiliated Hospital, Center for Translational Medicine, Sun Yat-sen UniversityAbstract Adipocyte dysfunction correlates with the development of diabetes. Here we show that mice with a adipocyte-specific deletion of the SUMO-specific protease SENP1 gene develop symptoms of type-1 diabetes mellitus (T1DM), including hyperglycaemia and glucose intolerance with mild insulin resistance. Peri-pancreatic adipocytes from SENP1-deficient mice exhibit heightened NF-κB activity and production of proinflammatory cytokines, which induce CCL5 expression in adjacent pancreatic islets and direct cytotoxic effects on pancreatic islets. Mechanistic studies show that SENP1 deletion in adipocytes enhances SUMOylation of the NF-κB essential molecule, NEMO, at lysine 277/309, leading to increased NF-κB activity, cytokine production and pancreatic inflammation. We further show that NF-κB inhibitors could inhibit pre-diabetic cytokine production, β-cell damages and ameliorate the T1DM phenotype in SENP1-deficient mice. Feeding a high-fat diet augments both type-1 and type-2 diabetes phenotypes in SENP1-deficient mice, consistent with the effects on adipocyte-derived NF-κB and cytokine signalling. Our study reveals previously unrecognized mechanism regulating the onset and progression of T1DM associated with adipocyte dysfunction.https://doi.org/10.1038/ncomms9917 |
| spellingShingle | Lan Shao Huanjiao Jenny Zhou Haifeng Zhang Lingfeng Qin John Hwa Zhong Yun Weidong Ji Wang Min SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression Nature Communications |
| title | SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression |
| title_full | SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression |
| title_fullStr | SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression |
| title_full_unstemmed | SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression |
| title_short | SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression |
| title_sort | senp1 mediated nemo desumoylation in adipocytes limits inflammatory responses and type 1 diabetes progression |
| url | https://doi.org/10.1038/ncomms9917 |
| work_keys_str_mv | AT lanshao senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT huanjiaojennyzhou senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT haifengzhang senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT lingfengqin senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT johnhwa senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT zhongyun senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT weidongji senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression AT wangmin senp1mediatednemodesumoylationinadipocyteslimitsinflammatoryresponsesandtype1diabetesprogression |