TY - JOUR

T1 - Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis and whole-body insulin sensitivity

AU - Shi, Hao

AU - Munk, Alexander

AU - Nielsen, Thomas Svava

AU - Daughtry, Morgan R

AU - Larsson, Louise

AU - Li, Shize

AU - Høyer, Kasper F

AU - Geisler, Hannah W

AU - Sulek, Karolina

AU - Kjøbsted, Rasmus

AU - Fisher, Taylor

AU - Andersen, Marianne M.

AU - Shen, Zhengxing

AU - Hansen, Ulrik K

AU - England, Eric M

AU - Cheng, Zhiyong

AU - Højlund, Kurt

AU - Wojtaszewski, Jørgen

AU - Yang, Xiaoyong

AU - Hulver, Matthew W

AU - Helm, Richard F

AU - Treebak, Jonas Thue

AU - Gerrard, David E

N1 - CURIS 2018 NEXS 098

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Faculty of Science

KW - O-GlcNAc signaling

KW - Type 2 diabetes

KW - N-acetyl-d-glucosamine

KW - Tissue cross talk

KW - Epigenetic regulation of Il15 transcription

KW - Insulin sensitivity

U2 - 10.1016/j.molmet.2018.02.010

DO - 10.1016/j.molmet.2018.02.010

M3 - Journal article

C2 - 29525407

VL - 11

SP - 160

EP - 177

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

ER -