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

• Published in: Molecular metabolism (Germany) 2018-05, Vol.11, p.160-177
• Main Authors: Shi, Hao, Munk, Alexander, Nielsen, Thomas S., Daughtry, Morgan R., Larsson, Louise, Li, Shize, Høyer, Kasper F., Geisler, Hannah W., Sulek, Karolina, Kjøbsted, Rasmus, Fisher, Taylor, Andersen, Marianne M., Shen, Zhengxing, Hansen, Ulrik K., England, Eric M., Cheng, Zhiyong, Højlund, Kurt, Wojtaszewski, Jørgen F.P., Yang, Xiaoyong, Hulver, Matthew W., Helm, Richard F., Treebak, Jonas T., Gerrard, David E.
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Animals; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Enhancer of Zeste Homolog 2 Protein - metabolism; Epigenetic regulation of Il15 transcription; Homeostasis; Humans; Insulin Resistance; Insulin sensitivity; Interleukin-15 - blood; Interleukin-15 - genetics; Interleukin-15 - metabolism; Mice; Muscle, Skeletal - metabolism; N-acetyl-d-glucosamine; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; O-GlcNAc signaling; Original; Tissue cross talk; Type 2 diabetes
• ISSN: 2212-8778; 2212-8778
• DOI: 10.1016/j.molmet.2018.02.010

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. 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. 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). 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. •Type 2 diabetic humans have elevated O-GlcNAc levels in skeletal muscle.•Knockout of OGT in muscle elevates whole body insulin sensitivity.•Knockout of OGT in muscle increases resistance to diet-induced obesity.•Muscle-specific OGT knockout mice have elevated plasma IL-15 levels.•OGT in muscle controls Il15 expression by O-GlcNAcylation and inhibition of EZH2.