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

Neuron. 2001 May;30(2):345-54. doi: 10.1016/s0896-6273(01)00293-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Carrier Proteins / metabolism*
  • Feeding and Eating Disorders / genetics*
  • Feeding and Eating Disorders / physiopathology
  • Female
  • Humans
  • Hypothalamus / pathology
  • Hypothalamus / physiopathology*
  • Intracellular Signaling Peptides and Proteins*
  • Machado-Joseph Disease / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Narcolepsy / genetics*
  • Narcolepsy / physiopathology
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / pathology
  • Neurons / physiology*
  • Neuropeptides / metabolism*
  • Neurotransmitter Agents / metabolism*
  • Nuclear Proteins
  • Obesity / genetics*
  • Obesity / physiopathology
  • Orexins
  • Peptides / genetics
  • Repressor Proteins
  • Sequence Deletion
  • Sleep Stages / genetics*
  • Sleep Stages / physiology
  • Sleep, REM / genetics
  • Transcription Factors

Substances

  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Neurotransmitter Agents
  • Nuclear Proteins
  • Orexins
  • Peptides
  • Repressor Proteins
  • Transcription Factors
  • polyglutamine
  • ATXN3 protein, human
  • Ataxin-3
  • Atxn3 protein, mouse