Sleep disorders, obesity, and aging: the role of orexin

Ageing Res Rev. 2015 Mar:20:63-73. doi: 10.1016/j.arr.2014.11.001. Epub 2014 Nov 22.


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.

Keywords: Aging; Energy balance; Hypocretin; Obesity; Orexin; Sleep.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Aging / physiology*
  • Animals
  • Disease Models, Animal
  • Energy Metabolism
  • Homeostasis / physiology
  • Humans
  • Hypothalamus / metabolism
  • Hypothalamus / physiopathology
  • Intracellular Signaling Peptides and Proteins* / metabolism
  • Intracellular Signaling Peptides and Proteins* / pharmacology
  • Neuropeptides* / metabolism
  • Neuropeptides* / pharmacology
  • Neurotransmitter Agents / metabolism
  • Neurotransmitter Agents / pharmacology
  • Obesity* / drug therapy
  • Obesity* / metabolism
  • Orexins
  • Signal Transduction
  • Sleep / drug effects
  • Sleep / physiology
  • Sleep Wake Disorders* / drug therapy
  • Sleep Wake Disorders* / metabolism


  • HCRT protein, human
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptides
  • Neurotransmitter Agents
  • Orexins