hypocretin1

Hypocretin-1, also known as orexin-A, is a neuropeptide of 33 amino acids produced in the lateral hypothalamus from the precursor prepro-orexin. Along with hypocretin-2 (orexin-B), hypocretin-1 is synthesized by neurons that project widely throughout the brain and regulate arousal, energy homeostasis, feeding, reward, and autonomic function. The two peptides are derived from the same precursor and are often studied together as the hypocretin/orexin system.

Hypocretin-1 exerts its effects by binding to two G-protein-coupled receptors, OX1R and OX2R, with orexin-A showing higher affinity for OX1R. Through these receptors, hypocretin-1 promotes wakefulness and motivated behaviors, and it modulates REM and non-REM sleep architecture. Orexin neurons interact with multiple arousal systems, including histaminergic, noradrenergic, serotonergic, and dopaminergic pathways, contributing to sustained attention and alertness.

Clinical significance is most evident in narcolepsy type 1, where there is a loss of orexin-producing neurons. Patients typically exhibit low cerebrospinal fluid (CSF) hypocretin-1 levels, with a commonly cited diagnostic threshold around 110 pg/mL. CSF hypocretin-1 measurement is used to support diagnosis in patients with suspected narcolepsy with cataplexy but is not universally abnormal in all sleep disorders.

Therapeutically, antagonists of orexin receptors (such as suvorexant and lemborexant) are approved for the treatment of insomnia, reflecting the role of hypocretin signaling in maintaining wakefulness. Research continues into orexin receptor agonists as a potential strategy to treat narcolepsy or other conditions characterized by excessive sleepiness.