Molecular and Developmental Biological Research on Roles of a novel neuropeptide, Orexin

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We have been studying roles of orexin-expressing neurons in the regulation of feeding behavior and wakefulness by means of transgenic technique. 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.We also demonstrated that orexin-containing neurons are able to monitor peripherally generated indicators of nutritional state, and are necessary for normal augmentation of arousal in response to fasting. Electrophysiological studies of isolated orexin neurons, which are specifically labeled by expression of green fluorescent protein in orexin/EGFP transgenic mice, revealed that activity of these neurons is inhibited by extracellular glucose and the adipostat leptin, and stimulated by the recently characterized gastrointestinal peptide ghrelin. Orexin neurons may provide a critical integrative link between peripheral metabolism and central regulation of behaviors required for an adaptive response to homeostatic challenges during times of scarcity.