Orexin neurons are indispensable for stress-induced thermogenesis in mice.
Orexin neurons contribute to cardiovascular, respiratory and analgesic components of the fight-or-flight response against stressors. Here, we examined whether the same is true for stress-induced hyperthermia. We used prepro-orexin knockout mice (ORX-KO) and orexin neuron-ablated mice (ORX-AB) in which the latter lack not only orexin, but also other putative neurotransmitter/modulators contained in the orexin neurons. In response to repetitive insertion of a temperature probe into their rectum (handling stress), ORX-KO mice showed a normal temperature change as compared to that of wild-type littermates (WT) while ORX-AB showed an attenuated response. Stress-induced expression of uncoupling protein-1, a key molecule in non-shivering thermogenesis in the brown adipose tissue (BAT), was also blunted in ORX-AB but not in ORX-KO. When the BAT was directly activated by a β3 adrenergic agonist, there was no difference in the resultant BAT temperature among the groups, indicating that BAT per se was normal in ORX-AB. In WT and ORX-KO, handling stress activated orexin neurons (as revealed by increased expression of c-Fos) and the resultant hyperthermia was largely blunted by pre-treatment with a β3 antagonist. This observation further supports the notion that attenuated stress-induced hyperthermia in ORX-AB mice was caused by a loss of orexin neurons and abnormal BAT regulation. This study pointed out, for the first time, the possible importance of co-existent neurotransmitter/modulators in the orexin neurons for stress-induced hyperthermia and the importance of integrity of the orexin neurons for full expression of multiple facets of the fight-or-flight response.
Zhang
Wei
W
Department of Molecular and Integrative Physiology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
Sunanaga
Jinko
J
Takahashi
Yoshiko
Y
Mori
Taketsugu
T
Sakurai
Takeshi
T
Kanmura
Yuichi
Y
Kuwaki
Tomoyuki
T
D055011:Ablation Techniques; D000222:Adaptation, Physiological / Q000502:physiology; D002001:Adipose Tissue, Brown / Q000502:physiology; D000818:Animals; D001831:Body Temperature / Q000502:physiology; D001833:Body Temperature Regulation / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D007473:Ion Channels / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000502:physiology; D023421:Models, Animal; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D022722:Thermogenesis / Q000502:physiology*; D000071256:Uncoupling Protein 1
D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D024101:Mitochondrial Proteins; D009479:Neuropeptides; D000068797:Orexins; D016760:Proto-Oncogene Proteins c-fos; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1
Neuron. 1991 Nov;7(5):703-16
1742021
J Comp Neurol. 2005 May 2;485(2):127-42
15776447
Acta Physiol (Oxf). 2010 Mar;198(3):223-35
19723027
Neurosci Lett. 2005 Jun 3;380(3):239-42
15862893
Am J Physiol Regul Integr Comp Physiol. 2003 Sep;285(3):R581-93
12750151
Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R533-40
16556901
Bull Exp Biol Med. 2001 Jan;131(1):60-3
11329085
J Comp Neurol. 2003 Oct 27;465(4):593-603
12975818
Brain Res. 2009 Mar 25;1262:25-37
19368849
Histochem Cell Biol. 2005 Feb;123(2):147-56
15742197
Neuroscience. 2002;110(3):515-26
11906790
Sleep. 2009 Sep;32(9):1127-34
19750917
Neurosci Res. 2003 May;46(1):53-62
12725912
Auton Neurosci. 2008 Nov 3;142(1-2):11-6
18440283
Am J Physiol Regul Integr Comp Physiol. 2006 Sep;291(3):R589-95
16601257
J Neurosci. 2004 Jun 9;24(23):5370-80
15190110
Am J Physiol Regul Integr Comp Physiol. 2006 Jun;290(6):R1654-63
16410401
J Comp Neurol. 1998 Dec 28;402(4):442-59
9862320
Neurosci Biobehav Rev. 2007;31(1):41-59
16618509
J Comp Neurol. 2003 Jun 2;460(3):303-26
12692852
Nat Neurosci. 2007 Sep;10(9):1131-3
17676060
J Neuroendocrinol. 1999 Aug;11(8):653-63
10447804
Biochem Biophys Res Commun. 2000 Apr 2;270(1):318-23
10733946
Brain Res. 1996 Feb 26;710(1-2):271-4
8963669
Neuroreport. 2005 Jan 19;16(1):5-8
15618879
Genes Dev. 1989 Nov;3(11):1669-76
2606343
J Biol Chem. 1999 Jun 18;274(25):17771-6
10364220
Neuroreport. 2001 Feb 12;12(2):435-40
11209963
J Pharmacol Exp Ther. 1994 Feb;268(2):847-55
8113997
Physiol Rev. 2004 Jan;84(1):277-359
14715917
Brain Res. 1999 May 8;827(1-2):243-60
10320718
J Physiol. 2007 Jun 1;581(Pt 2):649-63
17379635
Physiol Behav. 1997 Sep;62(3):463-70
9272651
Pharmacol Rev. 1995 Mar;47(1):133-78
7784478
Respir Physiol Neurobiol. 2008 Dec 10;164(1-2):204-12
18455970
J Psychiatr Res. 2007 Oct;41(7):537-52
16777143
Am J Physiol Regul Integr Comp Physiol. 2008 Jul;295(1):R343-54
18463193
J Neurosci. 2009 Sep 23;29(38):11954-64
19776281
Trends Pharmacol Sci. 1996 Oct;17(10):373-81
8979772
Cell. 1999 Aug 20;98(4):437-51
10481909
J Neurosci. 2008 Mar 5;28(10):2495-505
18322094
Respir Physiol Neurobiol. 2009 Sep 30;168(3):295-302
19664728
Am J Physiol Regul Integr Comp Physiol. 2007 Jan;292(1):R47-63
16959861
J Appl Physiol (1985). 2008 Feb;104(2):499-507
18032578
Brain Res. 2001 Aug 3;909(1-2):68-74
11478922
J Neurosci. 1998 Dec 1;18(23):9996-10015
9822755
Br J Pharmacol. 1996 Feb;117(3):435-442
8821531
Psychopharmacology (Berl). 1990;101(2):255-61
1971957
Neuron. 2001 May;30(2):345-54
11394998
Auton Neurosci. 2006 Jun 30;126-127:139-45
16574499
Nat Neurosci. 2008 Jan;11(1):62-71
18084288
Respir Physiol Neurobiol. 2009 May 15;166(3):184-6
19442935
Neuroscience. 2003;119(4):1033-44
12831862
Neuropharmacology. 2006 Sep;51(3):426-37
16733059
Eur J Neurosci. 2009 Oct;30(8):1603-14
19811530
J Neurosci. 2001 Oct 1;21(19):RC168
11567079