Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity.
Orexins (hypocretins) are a pair of neuropeptides implicated in energy homeostasis and arousal. Recent reports suggest that loss of orexin-containing neurons occurs in human patients with narcolepsy. We generated transgenic mice in which orexin-containing neurons are ablated by orexinergic-specific expression of a truncated Machado-Joseph disease gene product (ataxin-3) with an expanded polyglutamine stretch. These mice showed a phenotype strikingly similar to human narcolepsy, including behavioral arrests, premature entry into rapid eye movement (REM) sleep, poorly consolidated sleep patterns, and a late-onset obesity, despite eating less than nontransgenic littermates. These results provide evidence that orexin-containing neurons play important roles in regulating vigilance states and energy homeostasis. Orexin/ataxin-3 mice provide a valuable model for studying the pathophysiology and treatment of narcolepsy.
Hara
J
J
Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Beuckmann
C T
CT
Nambu
T
T
Willie
J T
JT
Chemelli
R M
RM
Sinton
C M
CM
Sugiyama
F
F
Yagami
K
K
Goto
K
K
Yanagisawa
M
M
Sakurai
T
T
D000818:Animals; D000067699:Ataxin-3; D002352:Carrier Proteins / Q000378:metabolism*; D001068:Feeding and Eating Disorders / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000473:pathology / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins; D017827:Machado-Joseph Disease / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000235:genetics* / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009687:Nuclear Proteins; D009765:Obesity / Q000235:genetics* / Q000503:physiopathology; D000068797:Orexins; D010455:Peptides / Q000235:genetics; D012097:Repressor Proteins; D017384:Sequence Deletion; D012894:Sleep Stages / Q000235:genetics* / Q000502:physiology; D012895:Sleep, REM / Q000235:genetics; D014157:Transcription Factors
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D009687:Nuclear Proteins; D000068797:Orexins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; C097188:polyglutamine; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse