title: Regulation of hypothalamic signaling by tuberoinfundibular peptide of 39 residues is critical for the response to cold: a novel peptidergic mechanism of thermoregulation.
abstract: Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R-containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2°C for several hours. Mice lacking TIP39 signaling, either because of PTH2R-null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature.
authors.affiliation: Section On Fundamental Neuroscience, National Institute Of Mental Health, National Institutes Of Health, Bethesda, Maryland 20892, USA.
authors.forename: Eugene L
authors.initials: EL
authors.lastname: Dimitrov
authors.forename: Yoon Yi
authors.initials: YY
authors.lastname: Kim
authors.forename: Ted B
authors.initials: TB
authors.lastname: Usdin
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000235:genetics; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000235:genetics; D003080:Cold Temperature; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005968:Glutamate Decarboxylase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008845:Microinjections / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009248:Nadolol / Q000494:pharmacology; D009434:Neural Pathways / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044183:Receptor, Parathyroid Hormone, Type 2 / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013266:Stilbamidines / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D000319:Adrenergic beta-Antagonists; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D009479:Neuropeptides; D012333:RNA, Messenger; D044183:Receptor, Parathyroid Hormone, Type 2; D013266:Stilbamidines; D050599:Vesicular Glutamate Transport Protein 2; C400136:tuberoinfundibular peptide 39; D049452:Green Fluorescent Proteins; D009248:Nadolol; D001616:beta-Galactosidase; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1