PMID- 29525407
OWN - NLM
STAT- MEDLINE
DCOM- 20190411
LR  - 20210109
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 11
DP  - 2018 May
TI  - Skeletal muscle O-GlcNAc transferase is important for muscle energy homeostasis 
      and whole-body insulin sensitivity.
PG  - 160-177
LID - S2212-8778(17)31100-6 [pii]
LID - 10.1016/j.molmet.2018.02.010 [doi]
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.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
FAU - Shi, Hao
AU  - Shi H
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Munk, Alexander
AU  - Munk A
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark.
FAU - Nielsen, Thomas S
AU  - Nielsen TS
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark.
FAU - Daughtry, Morgan R
AU  - Daughtry MR
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Larsson, Louise
AU  - Larsson L
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark.
FAU - Li, Shize
AU  - Li S
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Hoyer, Kasper F
AU  - Hoyer KF
AD  - Section 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, Denmark.
FAU - Geisler, Hannah W
AU  - Geisler HW
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Sulek, Karolina
AU  - Sulek K
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark.
FAU - Kjobsted, Rasmus
AU  - Kjobsted R
AD  - Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, 
      Faculty of Science, University of Copenhagen, Copenhagen, DK2100, Denmark.
FAU - Fisher, Taylor
AU  - Fisher T
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Andersen, Marianne M
AU  - Andersen MM
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark.
FAU - Shen, Zhengxing
AU  - Shen Z
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Hansen, Ulrik K
AU  - Hansen UK
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark.
FAU - England, Eric M
AU  - England EM
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA.
FAU - Cheng, Zhiyong
AU  - Cheng Z
AD  - Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic 
      Institute and State University, Blacksburg, VA 24061, USA.
FAU - Hojlund, Kurt
AU  - Hojlund K
AD  - Department 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, Denmark.
FAU - Wojtaszewski, Jorgen F P
AU  - Wojtaszewski JFP
AD  - Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, 
      Faculty of Science, University of Copenhagen, Copenhagen, DK2100, Denmark.
FAU - Yang, Xiaoyong
AU  - Yang X
AD  - Department of Cellular and Molecular Physiology, Yale University School of 
      Medicine, New Haven, CT 06520, USA.
FAU - Hulver, Matthew W
AU  - Hulver MW
AD  - Department 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, USA.
FAU - Helm, Richard F
AU  - Helm RF
AD  - Department of Biochemistry, Virginia Polytechnic Institute and State University, 
      Blacksburg, VA 24061, USA.
FAU - Treebak, Jonas T
AU  - Treebak JT
AD  - Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic 
      Metabolic Research, Faculty of Health and Medical Sciences, University of 
      Copenhagen, Copenhagen, DK2200, Denmark. Electronic address: 
      jttreebak@sund.ku.dk.
FAU - Gerrard, David E
AU  - Gerrard DE
AD  - Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and 
      State University, Blacksburg, VA 24061, USA. Electronic address: dgerrard@vt.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180224
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Interleukin-15)
RN  - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
RN  - EC 2.1.1.43 (Ezh2 protein, mouse)
RN  - EC 2.4.1.- (N-Acetylglucosaminyltransferases)
SB  - IM
MH  - Adipose Tissue/metabolism
MH  - Animals
MH  - Diabetes Mellitus, Type 2/genetics/*metabolism
MH  - Enhancer of Zeste Homolog 2 Protein/metabolism
MH  - Homeostasis
MH  - Humans
MH  - *Insulin Resistance
MH  - Interleukin-15/blood/genetics/metabolism
MH  - Mice
MH  - Muscle, Skeletal/*metabolism
MH  - N-Acetylglucosaminyltransferases/genetics/*metabolism
PMC - PMC6001359
OTO - NOTNLM
OT  - Epigenetic regulation of Il15 transcription
OT  - Insulin sensitivity
OT  - N-acetyl-d-glucosamine
OT  - O-GlcNAc signaling
OT  - Tissue cross talk
OT  - Type 2 diabetes
EDAT- 2018/03/12 06:00
MHDA- 2019/04/12 06:00
PMCR- 2018/02/24
CRDT- 2018/03/12 06:00
PHST- 2018/01/18 00:00 [received]
PHST- 2018/02/18 00:00 [revised]
PHST- 2018/02/19 00:00 [accepted]
PHST- 2018/03/12 06:00 [pubmed]
PHST- 2019/04/12 06:00 [medline]
PHST- 2018/03/12 06:00 [entrez]
PHST- 2018/02/24 00:00 [pmc-release]
AID - S2212-8778(17)31100-6 [pii]
AID - 10.1016/j.molmet.2018.02.010 [doi]
PST - ppublish
SO  - Mol Metab. 2018 May;11:160-177. doi: 10.1016/j.molmet.2018.02.010. Epub 2018 Feb 
      24.