title: Glucose sensing mechanisms in hypothalamic cell models: glucose inhibition of AgRP synthesis and secretion.
abstract: Glucose-sensing neurons play a role in energy homeostasis, yet how orexigenic neurons sense glucose remains unclear. As models of glucose-inhibited (GI) neurons, mHypoE-29/1 and mHypoA-NPY/GFP cells express the essential orexigenic neuropeptide AgRP and glucose sensing machinery. Exposure to increasing concentrations of glucose or the glucose analog 2-deoxyglucose (2-DG) results in a decrease in AgRP mRNA levels. Taste receptor, Tas1R2 mRNA expression was reduced by glucose, whereas 2-DG reduced Tas1R3 mRNA levels. Increasing glucose concentrations elicited a rise in Akt and neuronal nitric oxide synthase (nNOS) phosphorylation, CaMKKβ levels, and a reduction of AMP-kinase alpha phosphorylation. Inhibitors of NOS and the cystic fibrosis transmembrane conductance regulator (CFTR) prevented a decrease in AgRP secretion with glucose, suggesting a pivotal role for nNOS and the CFTR in glucose-sensing. These models possess the hallmark characteristics of GI neurons, and can be used to disentangle the mechanisms by which orexigenic neurons sense glucose.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chalmers
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Janet J
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Cellular and Molecular Biology, Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5S 1A8, Canada. Electronic address: d.belsham@utoronto.ca.
authors.forename: Denise D
authors.initials: DD
authors.lastname: Belsham
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D054369:Agouti-Related Protein / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D015248:Gemfibrozil / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007031:Hypothalamus / Q000166:cytology* / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009478:Neuropeptide Y; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: D054369:Agouti-Related Protein; D009478:Neuropeptide Y; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C431926:taste receptors, type 1; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D049452:Green Fluorescent Proteins; D019289:Pyruvic Acid; D003847:Deoxyglucose; D052248:Nitric Oxide Synthase Type I; C558401:CPT1B protein, mouse; D002334:Carnitine O-Palmitoyltransferase; D051057:Proto-Oncogene Proteins c-akt; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000263:Adenylate Kinase; D005947:Glucose; D015248:Gemfibrozil
keywords: AMPK; Agouti-related peptide; Glucose; Hypothalamus; Neuropeptide