title: Characteristics and mechanisms of hypothalamic neuronal fatty acid sensing.
abstract: We assessed the mechanisms by which specialized hypothalamic ventromedial nucleus (VMN) neurons utilize both glucose and long-chain fatty acids as signaling molecules to alter their activity as a potential means of regulating energy homeostasis. Fura-2 calcium (Ca(2+)) and membrane potential dye imaging, together with pharmacological agents, were used to assess the mechanisms by which oleic acid (OA) alters the activity of dissociated VMN neurons from 3- to 4-wk-old rats. OA excited up to 43% and inhibited up to 29% of all VMN neurons independently of glucose concentrations. In those neurons excited by both 2.5 mM glucose and OA, OA had a concentration-dependent effective excitatory concentration (EC(50)) of 13.1 nM. Neurons inhibited by both 2.5 mM glucose and OA had an effective inhibitory concentration (IC(50)) of 93 nM. At 0.5 mM glucose, OA had markedly different effects on these same neurons. Inhibition of carnitine palmitoyltransferase, reactive oxygen species formation, long-chain acetyl-CoA synthetase and ATP-sensitive K(+) channel activity or activation of uncoupling protein 2 (UCP2) accounted for only approximately 20% of OA's excitatory effects and approximately 40% of its inhibitory effects. Inhibition of CD36, a fatty acid transporter that can alter cell function independently of intracellular fatty acid metabolism, reduced the effects of OA by up to 45%. Thus OA affects VMN neuronal activity through multiple pathways. In glucosensing neurons, its effects are glucose dependent. This glucose-OA interaction provides a potential mechanism whereby such "metabolic sensing" neurons can respond to differences in the metabolic states associated with fasting and feeding.
authors.affiliation: Neurology Service, VA Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095, USA.
authors.forename: Christelle
authors.initials: C
authors.lastname: Le Foll
authors.forename: Boman G
authors.initials: BG
authors.lastname: Irani
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.forename: Ambrose A
authors.initials: AA
authors.lastname: Dunn-Meynell
authors.forename: Barry E
authors.initials: BE
authors.lastname: Levin
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism; D020013:Calcium Signaling; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007473:Ion Channels / Q000378:metabolism; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D008856:Microscopy, Fluorescence; D024101:Mitochondrial Proteins / Q000378:metabolism; D009433:Neural Inhibition; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D000071246:Uncoupling Protein 2; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
chemical_list: D018955:CD36 Antigens; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007473:Ion Channels; D054086:KATP Channels; D024101:Mitochondrial Proteins; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; D019301:Oleic Acid; D002334:Carnitine O-Palmitoyltransferase; D003066:Coenzyme A Ligases; D005947:Glucose