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Mol Metab. 2018 May;11:160-177. doi: 10.1016/j.molmet.2018.02.010. Epub 2018 Feb 24.

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

Author information

1
Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
2
Section of Integrative Physiology, Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK2200, Denmark.
3
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.
4
Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, DK2100, Denmark.
5
Department of Human Nutrition, Foods, and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
6
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.
7
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
8
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.
9
Department of Biochemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
10
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.
11
Department of Animal and Poultry Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA. Electronic address: dgerrard@vt.edu.

Abstract

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:

Epigenetic regulation of Il15 transcription; Insulin sensitivity; N-acetyl-d-glucosamine; O-GlcNAc signaling; Tissue cross talk; Type 2 diabetes

PMID:
29525407
PMCID:
PMC6001359
DOI:
10.1016/j.molmet.2018.02.010
[Indexed for MEDLINE]
Free PMC Article

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