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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.

Pubmed ID: 11394998


  • Hara J
  • Beuckmann CT
  • Nambu T
  • Willie JT
  • Chemelli RM
  • Sinton CM
  • Sugiyama F
  • Yagami K
  • Goto K
  • Yanagisawa M
  • Sakurai T



Publication Data

May 7, 2001

Associated Grants


Mesh Terms

  • Animals
  • Carrier Proteins
  • Eating Disorders
  • Female
  • Humans
  • Hypothalamus
  • Intracellular Signaling Peptides and Proteins
  • Machado-Joseph Disease
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Narcolepsy
  • Nerve Tissue Proteins
  • Neurons
  • Neuropeptides
  • Neurotransmitter Agents
  • Nuclear Proteins
  • Obesity
  • Peptides
  • Repressor Proteins
  • Sequence Deletion
  • Sleep Stages
  • Sleep, REM
  • Transcription Factors