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

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.
Authors	J Hara, C T Beuckmann, T Nambu, J T Willie, R M Chemelli, C M Sinton, F Sugiyama, K Yagami, K Goto, M Yanagisawa, T Sakurai
Journal	Neuron (Neuron) Vol. 30 Issue 2 Pg. 345-54 (May 2001) ISSN: 0896-6273 [Print] United States
PMID	11394998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	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
Topics	Animals Ataxin-3 Carrier Proteins (metabolism) Feeding and Eating Disorders (genetics, physiopathology) Female Humans Hypothalamus (pathology, physiopathology) Intracellular Signaling Peptides and Proteins Machado-Joseph Disease (genetics) Male Mice Mice, Inbred C57BL Mice, Inbred DBA Mice, Transgenic Narcolepsy (genetics, physiopathology) Nerve Tissue Proteins (chemistry, genetics, metabolism) Neurons (pathology, physiology) Neuropeptides (metabolism) Neurotransmitter Agents (metabolism) Nuclear Proteins Obesity (genetics, physiopathology) Orexins Peptides (genetics) Repressor Proteins Sequence Deletion Sleep Stages (genetics, physiology) Sleep, REM (genetics) Transcription Factors

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