title: Glucokinase inhibitor glucosamine stimulates feeding and activates hypothalamic neuropeptide Y and orexin neurons.
abstract: Maintaining glucose levels within the appropriate physiological range is necessary for survival. The identification of specific neuronal populations, within discreet brain regions, sensitive to changes in glucose concentration has led to the hypothesis of a central glucose-sensing system capable of directly modulating feeding behaviour. Glucokinase (GK) has been identified as a glucose-sensor responsible for detecting such changes both within the brain and the periphery. We previously reported that antagonism of centrally expressed GK by administration of glucosamine (GSN) was sufficient to induce protective glucoprivic feeding in rats. Here we examine a neurochemical mechanism underlying this effect and report that GSN stimulated food intake is highly correlated with the induction of the neuronal activation marker cFOS within two nuclei with a demonstrated role in central glucose sensing and appetite, the arcuate nucleus of the hypothalamus (ARC) and lateral hypothalamic area (LHA). Furthermore, GSN stimulated cFOS within the ARC was observed in orexigenic neurons expressing the endogenous melanocortin receptor antagonist agouti-related peptide (AgRP) and neuropeptide Y (NPY), but not those expressing the anorectic endogenous melanocortin receptor agonist alpha-melanocyte stimulating hormone (α-MSH). In the LHA, GSN stimulated cFOS was found within arousal and feeding associated orexin/hypocretin (ORX), but not orexigenic melanin-concentrating hormone (MCH) expressing neurons. Our data suggest that GK within these specific feeding and arousal related populations of AgRP/NPY and ORX neurons may play a modulatory role in the sensing of and appetitive response to hypoglycaemia.
authors: Department of Pharmacology, University of Cambridge, Cambridge, Tennis Court Road, Cambridge CB2 1PD, UK.
authors: Ligang
authors: L
authors: Zhou
authors: Chen-Yu
authors: CY
authors: Yueh
authors: Daniel D
authors: DD
authors: Lam
authors: Jill
authors: J
authors: Shaw
authors: Mayowa
authors: M
authors: Osundiji
authors: Alastair S
authors: AS
authors: Garfield
authors: Mark
authors: M
authors: Evans
authors: Lora K
authors: LK
authors: Heisler
mesh_terms: D054369:Agouti-Related Protein / Q000378:metabolism; D000818:Animals; D004435:Eating / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005944:Glucosamine / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D009478:Neuropeptide Y / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013223:Statistics as Topic
chemical_list: D054369:Agouti-Related Protein; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; D005944:Glucosamine