title: N-glycan remodeling on glucagon receptor is an effector of nutrient sensing by the hexosamine biosynthesis pathway.
abstract: Glucose homeostasis in mammals is dependent on the opposing actions of insulin and glucagon. The Golgi N-acetylglucosaminyltransferases encoded by Mgat1, Mgat2, Mgat4a/b/c, and Mgat5 modify the N-glycans on receptors and solute transporter, possibly adapting activities in response to the metabolic environment. Herein we report that Mgat5(-/-) mice display diminished glycemic response to exogenous glucagon, together with increased insulin sensitivity. Glucagon receptor signaling and gluconeogenesis in Mgat5(-/-) cultured hepatocytes was impaired. In HEK293 cells, signaling by ectopically expressed glucagon receptor was increased by Mgat5 expression and GlcNAc supplementation to UDP-GlcNAc, the donor substrate shared by Mgat branching enzymes. The mobility of glucagon receptor in primary hepatocytes was reduced by galectin-9 binding, and the strength of the interaction was dependent on Mgat5 and UDP-GlcNAc levels. Finally, oral GlcNAc supplementation rescued the glucagon response in Mgat5(-/-) hepatocytes and mice, as well as glycolytic metabolites and UDP-GlcNAc levels in liver. Our results reveal that the hexosamine biosynthesis pathway and GlcNAc salvage contribute to glucose homeostasis through N-glycan branching on glucagon receptor.
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and.
authors.forename: Anita
authors.initials: A
authors.lastname: Johswich
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and.
authors.forename: Christine
authors.initials: C
authors.lastname: Longuet
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and.
authors.forename: Judy
authors.initials: J
authors.lastname: Pawling
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and.
authors.forename: Anas
authors.initials: A
authors.lastname: Abdel Rahman
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and the Departments of Molecular Genetics.
authors.forename: Michael
authors.initials: M
authors.lastname: Ryczko
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and Medicine, University of Toronto, Toronto, Ontario M5R 0A3, Canada.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
authors.affiliation: From the Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada and the Departments of Molecular Genetics, Laboratory Medicine and Pathology, and Medicine, University of Toronto, Toronto, Ontario M5R 0A3, Canada dennis@lunenfeld.ca.
authors.forename: James W
authors.initials: JW
authors.lastname: Dennis
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid; D005934:Glucagon / Q000494:pharmacology; D057809:HEK293 Cells; D006595:Hexosamines / Q000096:biosynthesis*; D006801:Humans; D007003:Hypoglycemia / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics / Q000378:metabolism; D011134:Polysaccharides / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D006595:Hexosamines; D011134:Polysaccharides; D018027:Receptors, Glucagon; D005934:Glucagon; D017351:N-Acetylglucosaminyltransferases; C052254:alpha-1,6-mannosylglycoprotein beta 1,6-N-acetylglucosaminyltransferase
keywords: Glucagon Receptor; Gluconeogenesis; Glycosylation; Glycosyltransferase; Golgi N-Acetylglucosaminyltransferases; Metabolism; Receptor Regulation
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