The hypothalamic
neuropeptides orexin A and B (
hypocretin 1 and 2) are important homeostatic mediators of central control of energy metabolism and maintenance of sleep/wake states. Dysregulation or loss of
orexin signaling has been linked to
narcolepsy,
obesity, and age-related disorders. In this review, we present an overview of our current understanding of
orexin function, focusing on
sleep disorders, energy balance, and aging, in both rodents and humans. We first discuss animal models used in studies of
obesity and sleep, including loss of function using transgenic or viral-mediated approaches, gain of function models using exogenous delivery of
orexin receptor agonist, and naturally-occurring models in which
orexin responsiveness varies by individual. We next explore rodent models of
orexin in aging, presenting evidence that
orexin loss contributes to age-related changes in sleep and energy balance. In the next section, we focus on clinical importance of
orexin in human
obesity, sleep, and aging. We include discussion of
orexin loss in
narcolepsy and potential importance of
orexin in
insomnia, correlations between animal and human studies of age-related decline, and evidence for
orexin involvement in age-related changes in cognitive performance. Finally, we present a summary of recent studies of
orexin in
neurodegenerative disease. We conclude that
orexin acts as an integrative homeostatic signal influencing numerous brain regions, and that this pivotal role results in potential dysregulation of multiple physiological processes when
orexin signaling is disrupted or lost.