Orexin A and orexin B constitute a novel distinct peptide family, showing no significant homology with any other peptides. Structural analysis of purified peptide showed that orexin A is a 33-amino-acid peptide with an N-terminal pyroglutamyl

Lateral hypothalamic neuropeptides, orexins, have been recognized as one of the most important regulators of sleep/wakefulness states. Besides, these peptides are also regarded as an important factor that regulates feeding behavior, owing to their localization within the lateral hypothalamic area, the classic “feeding center”, pharmacological activities, and the fact that prepro-orexin mRNA is upregulated when animals are fasted. This review summarizes the role of orexins in the regulation of feeding behavior and body weight homeostasis in relation to other systems that involve orexinergic neurotransmission. Introduction Orexins are hypothalamic neuropeptides identified in 1998. Several studies showed that orexin deficiency causes narcolepsy in humans and animals, implicating these hypothalamic neuropeptides in play a critical role in the regulation of sleep/wakefulness states. However, orexins were initially recognized as regulators of feeding behavior, firstly because of their exclusive production in the lateral hypothalamic area (LHA), a region known as the “feeding center”, and secondly because of their pharmacological activity; intracerebroventricular (ICV) injection of orexins induced feeding behavior in rats and mice. Recent studies suggested that further orexins play further roles in the coordination of emotion, energy homeostasis, reward system, drug addiction, and arousal. This review focuses especially on the role of orexins in the regulation of 2 feeding, body weight and energy homeostasis in relation to other systems in which orexins are shown to be involved (Fig. 1). 1.Overview of the orexin system 1-1.Orexins and their structures In 1998, we identified novel neuropeptides, orexin A and orexin B, from rat brain extracts as two endogenous ligands for two orphan G-protein-coupled receptors by a method so-called "reverse pharmacology", which utilized receptor-expressing cell lines as the assay system. Molecular cloning studies showed that both orexin A and orexin B are derived from a common precursor peptide, prepro-orexin. An mRNA encoding the same precursor peptide was independently identified by de Lecea et al. as a hypothalamus-specific transcript. de Lecea et al. predicted that the transcript encoded a polypeptide precursor that is proteolytically cleaved to produce two isopeptides, and named them as hypocretin-1 and hypocretin-2 (corresponding to orexin A and orexin B, respectively). Orexin A and orexin B constitute a novel distinct peptide family, showing no significant homology with any other peptides. Structural analysis of purified peptide showed that orexin A is a 33-amino-acid peptide with an N-terminal pyroglutamyl