Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity
Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-05-01
|
| Series: | Molecular Metabolism |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877817311006 |
| _version_ | 1818060288556007424 |
|---|---|
| author | Hao Shi Alexander Munk Thomas S. Nielsen Morgan R. Daughtry Louise Larsson Shize Li Kasper F. Høyer Hannah W. Geisler Karolina Sulek Rasmus Kjøbsted Taylor Fisher Marianne M. Andersen Zhengxing Shen Ulrik K. Hansen Eric M. England Zhiyong Cheng Kurt Højlund Jørgen F.P. Wojtaszewski Xiaoyong Yang Matthew W. Hulver Richard F. Helm Jonas T. Treebak David E. Gerrard |
| author_facet | Hao Shi Alexander Munk Thomas S. Nielsen Morgan R. Daughtry Louise Larsson Shize Li Kasper F. Høyer Hannah W. Geisler Karolina Sulek Rasmus Kjøbsted Taylor Fisher Marianne M. Andersen Zhengxing Shen Ulrik K. Hansen Eric M. England Zhiyong Cheng Kurt Højlund Jørgen F.P. Wojtaszewski Xiaoyong Yang Matthew W. Hulver Richard F. Helm Jonas T. Treebak David E. Gerrard |
| author_sort | Hao Shi |
| collection | DOAJ |
| description | Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. Keywords: O-GlcNAc signaling, Type 2 diabetes, N-acetyl-d-glucosamine, Tissue cross talk, Epigenetic regulation of Il15 transcription, Insulin sensitivity |
| first_indexed | 2024-12-10T13:30:02Z |
| format | Article |
| id | doaj.art-261b3cbf836f43468337bc9950698585 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-10T13:30:02Z |
| publishDate | 2018-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-261b3cbf836f43468337bc99506985852022-12-22T01:47:01ZengElsevierMolecular Metabolism2212-87782018-05-0111160177Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivityHao Shi0Alexander Munk1Thomas S. Nielsen2Morgan R. Daughtry3Louise Larsson4Shize Li5Kasper F. Høyer6Hannah W. Geisler7Karolina Sulek8Rasmus Kjøbsted9Taylor Fisher10Marianne M. Andersen11Zhengxing Shen12Ulrik K. Hansen13Eric M. England14Zhiyong Cheng15Kurt Højlund16Jørgen F.P. Wojtaszewski17Xiaoyong Yang18Matthew W. Hulver19Richard F. Helm20Jonas T. Treebak21David E. Gerrard22Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, DenmarkSection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, DenmarkDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, DenmarkDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, DK8000, DenmarkDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, DK2100, DenmarkDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, DenmarkDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, DenmarkDepartment of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USADepartment of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USADepartment of Endocrinology, Odense University Hospital, Odense, Denmark; Section of Molecular Diabetes and Metabolism, Institute of Molecular Medicine and Institute of Clinical Research, University of Southern Denmark, Odense, DenmarkSection of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, DK2100, DenmarkDepartment of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USADepartment of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA; The Virginia Tech Metabolic Phenotyping Core, Blacksburg, VA 24061, USADepartment of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USASection of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, Denmark; Corresponding author.Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA; Corresponding author.Objective: Given that cellular O-GlcNAcylation levels are thought to be real-time measures of cellular nutrient status and dysregulated O-GlcNAc signaling is associated with insulin resistance, we evaluated the role of O-GlcNAc transferase (OGT), the enzyme that mediates O-GlcNAcylation, in skeletal muscle. Methods: We assessed O-GlcNAcylation levels in skeletal muscle from obese, type 2 diabetic people, and we characterized muscle-specific OGT knockout (mKO) mice in metabolic cages and measured energy expenditure and substrate utilization pattern using indirect calorimetry. Whole body insulin sensitivity was assessed using the hyperinsulinemic euglycemic clamp technique and tissue-specific glucose uptake was subsequently evaluated. Tissues were used for histology, qPCR, Western blot, co-immunoprecipitation, and chromatin immunoprecipitation analyses. Results: We found elevated levels of O-GlcNAc-modified proteins in obese, type 2 diabetic people compared with well-matched obese and lean controls. Muscle-specific OGT knockout mice were lean, and whole body energy expenditure and insulin sensitivity were increased in these mice, consistent with enhanced glucose uptake and elevated glycolytic enzyme activities in skeletal muscle. Moreover, enhanced glucose uptake was also observed in white adipose tissue that was browner than that of WT mice. Interestingly, mKO mice had elevated mRNA levels of Il15 in skeletal muscle and increased circulating IL-15 levels. We found that OGT in muscle mediates transcriptional repression of Il15 by O-GlcNAcylating Enhancer of Zeste Homolog 2 (EZH2). Conclusions: Elevated muscle O-GlcNAc levels paralleled insulin resistance and type 2 diabetes in humans. Moreover, OGT-mediated signaling is necessary for proper skeletal muscle metabolism and whole-body energy homeostasis, and our data highlight O-GlcNAcylation as a potential target for ameliorating metabolic disorders. Keywords: O-GlcNAc signaling, Type 2 diabetes, N-acetyl-d-glucosamine, Tissue cross talk, Epigenetic regulation of Il15 transcription, Insulin sensitivityhttp://www.sciencedirect.com/science/article/pii/S2212877817311006 |
| spellingShingle | Hao Shi Alexander Munk Thomas S. Nielsen Morgan R. Daughtry Louise Larsson Shize Li Kasper F. Høyer Hannah W. Geisler Karolina Sulek Rasmus Kjøbsted Taylor Fisher Marianne M. Andersen Zhengxing Shen Ulrik K. Hansen Eric M. England Zhiyong Cheng Kurt Højlund Jørgen F.P. Wojtaszewski Xiaoyong Yang Matthew W. Hulver Richard F. Helm Jonas T. Treebak David E. Gerrard Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity Molecular Metabolism |
| title | Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity |
| title_full | Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity |
| title_fullStr | Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity |
| title_full_unstemmed | Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity |
| title_short | Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity |
| title_sort | skeletal muscle o glcnac transferase is important for muscle energy homeostasis and whole body insulin sensitivity |
| url | http://www.sciencedirect.com/science/article/pii/S2212877817311006 |
| work_keys_str_mv | AT haoshi skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT alexandermunk skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT thomassnielsen skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT morganrdaughtry skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT louiselarsson skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT shizeli skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT kasperfhøyer skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT hannahwgeisler skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT karolinasulek skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT rasmuskjøbsted skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT taylorfisher skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT mariannemandersen skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT zhengxingshen skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT ulrikkhansen skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT ericmengland skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT zhiyongcheng skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT kurthøjlund skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT jørgenfpwojtaszewski skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT xiaoyongyang skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT matthewwhulver skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT richardfhelm skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT jonasttreebak skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity AT davidegerrard skeletalmuscleoglcnactransferaseisimportantformuscleenergyhomeostasisandwholebodyinsulinsensitivity |