title: Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity.
abstract: Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Jessica T Y
authors.initials: JT
authors.lastname: Yue
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.|Departments of Physiology, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Mona A
authors.initials: MA
authors.lastname: Abraham
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.|Departments of Physiology, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Paige V
authors.initials: PV
authors.lastname: Bauer
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.|Departments of Physiology, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Mary P
authors.initials: MP
authors.lastname: LaPierre
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Peili
authors.initials: P
authors.lastname: Wang
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Frank A
authors.initials: FA
authors.lastname: Duca
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Filippi
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Owen
authors.initials: O
authors.lastname: Chan
authors.affiliation: Toronto General Hospital Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.|Departments of Physiology, Toronto, Ontario, Canada M5S 1A8.|Departments of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.|Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced*; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D038321:Glycemic Index; D050487:Glycine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D007736:Kynurenic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000008:administration & dosage*
chemical_list: D050487:Glycine Plasma Membrane Transport Proteins; D044067:Receptors, Lipoxin; C493267:Slc6a9 protein, mouse; C493266:Slc6a9 protein, rat; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid