Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity

Junko Hara, Carsten T. Beuckmann, Tadahiro Nambu, Jon T. Willie, Richard M. Chemelli, Christopher M. Sinton, Fumihiro Sugiyama, Ken Ichi Yagami, Katsutoshi Goto, Masashi Yanagisawa, Takeshi Sakurai

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1030 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)345-354
Number of pages10
JournalNeuron
Volume30
Issue number2
DOIs
StatePublished - Jan 1 2001

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Hara, J., Beuckmann, C. T., Nambu, T., Willie, J. T., Chemelli, R. M., Sinton, C. M., Sugiyama, F., Yagami, K. I., Goto, K., Yanagisawa, M., & Sakurai, T. (2001). Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 30(2), 345-354. https://doi.org/10.1016/S0896-6273(01)00293-8