title: Thermosensing mechanisms and their impairment by high-fat diet in orexin neurons.
abstract: In homeotherms, the hypothalamus controls thermoregulatory and adaptive mechanisms in energy balance, sleep-wake and locomotor activity to maintain optimal body temperature. Orexin neurons may be involved in these functions as they promote thermogenesis, food intake and behavioral arousal, and are sensitive to temperature and metabolic status. How thermal and energy balance signals are integrated in these neurons is unknown. Thus, we investigated the cellular mechanisms of thermosensing in orexin neurons and their response to a change in energy status using whole-cell patch clamp on rat brain slices. We found that warming induced an increase in miniature excitatory postsynaptic current (EPSC) frequency, which was blocked by the transient receptor potential vanilloid-1 (TRPV1) receptor antagonist AMG9810 and mimicked by its agonist capsaicin, suggesting that the synaptic effect is mediated by heat-sensitive TRPV1 channels. Furthermore, warming inhibits orexin neurons by activating ATP-sensitive potassium (KATP) channels, an effect regulated by uncoupling protein 2 (UCP2), as the UCP2 inhibitor genipin abolished this response. These properties are unique to orexin neurons in the lateral hypothalamus, as neighboring melanin-concentrating hormone neurons showed no response to warming within the physiological temperature range. Interestingly, in rats fed with western diet for 1 or 11weeks, orexin neurons had impaired synaptic and KATP response to warming. In summary, this study reveals several mechanisms underlying thermosensing in orexin neurons and their attenuation by western diet. Overeating induced by western diet may in part be due to impaired orexin thermosensing, as post-prandial thermogenesis may promote satiety and lethargy by inhibiting orexin neurons.
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Belanger-Willoughby
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Linehan
authors.affiliation: Division of Biomedical Sciences, Faculty of Medicine, Memorial University, St. John's, Newfoundland A1B 3V6, Canada. Electronic address: michiru@mun.ca.
authors.forename: M
authors.initials: M
authors.lastname: Hirasawa
mesh_terms: D000178:Acrylamides / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006358:Hot Temperature; D007026:Hypothalamic Area, Lateral / Q000187:drug effects / Q000503:physiopathology; D007028:Hypothalamic Hormones / Q000378:metabolism; D039823:Iridoids / Q000494:pharmacology; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000378:metabolism; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D000068797:Orexins / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010907:Pituitary Hormones / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013697:Thermosensing / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques; D000071246:Uncoupling Protein 2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C500530:3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)acrylamide; D000178:Acrylamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007028:Hypothalamic Hormones; D039823:Iridoids; D054086:KATP Channels; D008543:Melanins; D018377:Neurotransmitter Agents; D000068797:Orexins; D010907:Pituitary Hormones; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C000604391:Ucp2 protein, rat; D000071246:Uncoupling Protein 2; C019463:melanin-concentrating hormone; C007834:genipin; D002211:Capsaicin
keywords: neuronal thermosensing; orexin neurons; transient receptor potential vanilloid-1; western diet