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 RIS Download
Animals | Ataxin-3 | Carrier Proteins | Feeding and 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 | Orexins | Peptides | Repressor Proteins | Sequence Deletion | Sleep Stages | Sleep, REM | Transcription Factors