title: An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis.
abstract: Orexin (hypocretin) neurons, located exclusively in the PeF-LH, which includes the perifornical area (PeF), the lateral hypothalamus (LH), and lateral portions of the medial hypothalamus, have widespread projections and influence many physiological functions, including the autonomic regulation of body temperature and energy metabolism. Narcolepsy is characterized by the loss of orexin neurons and by disrupted sleep, but also by dysregulation of body temperature and by a strong tendency for obesity. Heat production (thermogenesis) in brown adipose tissue (BAT) contributes to the maintenance of body temperature and, through energy consumption, to body weight regulation. We identified a neural substrate for the influence of orexin neurons on BAT thermogenesis in rat. Nanoinjection of orexin-A (12 pmol) into the rostral raphe pallidus (rRPa), the site of BAT sympathetic premotor neurons, produced large, sustained increases in BAT sympathetic outflow and in BAT thermogenesis. Activation of neurons in the PeF-LH also enhanced BAT thermogenesis over a long time course. Combining viral retrograde tracing from BAT, or cholera toxin subunit b tracing from rRPa, with orexin immunohistochemistry revealed synaptic connections to BAT from orexin neurons in PeF-LH and from rRPa neurons with closely apposed, varicose orexin fibers, as well as a direct, orexinergic projection from PeF-LH to rRPa. These results indicate a potent modulation of BAT thermogenesis by orexin released from the terminals of orexin neurons in PeF-LH directly into the rRPa and provide a potential mechanism contributing to the disrupted regulation of body temperature and energy metabolism in the absence of orexin.
authors: Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon 97239-3098, USA. tupone@ohsu.edu
authors: Domenico
authors: D
authors: Tupone
authors: Christopher J
authors: CJ
authors: Madden
authors: Georgina
authors: G
authors: Cano
authors: Shaun F
authors: SF
authors: Morrison
mesh_terms: D002001:Adipose Tissue, Brown / Q000502:physiology*; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D002772:Cholera Toxin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005917:Globus Pallidus / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000166:cytology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008845:Microinjections / Q000379:methods; D016202:N-Methylaspartate / Q000494:pharmacology; D009287:Naphthyridines; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D000068797:Orexins; D011137:Polystyrenes / Q000008:administration & dosage; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D022722:Thermogenesis / Q000187:drug effects / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins; D011137:Polystyrenes; D016202:N-Methylaspartate; D014508:Urea; D002772:Cholera Toxin; D001616:beta-Galactosidase