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Glycobiology Advance Access originally published online on May 4, 2007
Glycobiology 2007 17(8):828-837; doi:10.1093/glycob/cwm048
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Metabolic homeostasis and tissue renewal are dependent on ß1,6GlcNAc-branched N-glycans

Pam Cheung2,3, Judy Pawling2, Emily A Partridge2,4, Balram Sukhu2, Marc Grynpas2,4 and James W Dennis1,3,4

2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue R988, Toronto, ON, Canada M5G 1X5
3 Department of Molecular and Medical Genetics
4 Department of Laboratory Medicine and Pathology, University of Toronto, Canada

1 To whom correspondence should be addressed; Tel: +1-416-586-8233; Fax: +1-416-586-8588; e-mail: dennis{at}mshri.on.ca

Received on January 25, 2007; revised on March 22, 2007; accepted on April 19, 2007

Golgi ß1,6-N-acetylglucosaminyltransferase V (Mgat5) produces ß1,6GlcNAc-branched N-glycans on glycoproteins, which increases their affinity for galectins and opposes loss from the cell surface to constitutive endocytosis. Oncogenic transformation increases Mgat5 expression, increases ß1,6GlcNAc-branched N-glycans on epidermal growth factor and transforming growth factor-ß receptors, and enhances sensitivities to ligands, cell motility, and tumor metastasis. Here, we demonstrate that Mgat5–/– mouse embryonic fibroblasts (MEFs) display reduced sensitivity to anabolic cytokines and reduced glucose uptake and proliferation. Mgat5–/– mice are also hypoglycemic, resistant to weight gain on a calorie-enriched diet, hypersensitive to fasting, and display increased oxidative respiration and reduced fecundity. Serum-dependent activation of the extracellular response kinase (growth) and Smad2/3 (arrest) pathways in Mgat5–/– MEFs and bone marrow cells reveals an imbalance favoring arrest. Mgat5–/– mice have fewer muscle satellite cells, less osteogenic activity in bone marrow, and accelerated loss of muscle and bone mass with aging. Our results suggest that ß1,6GlcNAc-branched N-glycans promote sensitivity to anabolic cytokines, and increase fat stores, tissue renewal, and longevity.

Key words: aging / cytokine signaling / metabolism / Mgat5 / N-glycans / stem cells


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