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Glycobiology Advance Access published online on May 4, 2007
Glycobiology, 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 Cheung1,2, Judy Pawling1, Emily A. Partridge1,3, Balram Sukhu1, Marc Grynpas1,3 and James W. Dennis1,2,3,

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

Phone: 416-586-8233, FAX: 416-586-8588, Email: Dennis{at}mshri.on.ca

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

Golgi ß1,6N-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, ß1,6GlcNAc-branched N-glycans on EGF and TGF-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, reduced glucose uptake and proliferation. Mgat5-/- mice are also hypoglycaemic, resistant to weight-gain on a calorie-enriched diet, hypersensitive to fasting, display increased oxidative respiration and reduced fecundity. Serum-dependent activation of the Erk (growth) and Smad2/3 (arrest) pathways in Mgat5-/- MEFs and bone marrow cells reveals an imbalance favouring the latter. Mgat5-/- mice have fewer muscle satellite cells and 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, increased fat stores, tissue renewal and longevity.


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