Discovery of the Orexins: Two New Brain Peptides That Control Hunger and Feeding

The researchers used a combination of molecular biology techniques to identify orexin-A and orexin-B. They screened orphan G protein-coupled receptors, purified the peptides that activated them, identified their precursor gene, mapped where they were produced in the rat brain using mRNA localization and immunohistochemistry, and tested their effects on feeding behavior through central (brain) administration in rats.

This is one of the most important neuropeptide discoveries of the late 20th century. Orexins (also called hypocretins) turned out to control not just appetite but also wakefulness, reward, and arousal. The loss of orexin-producing neurons was later found to cause narcolepsy. This single paper launched an entire field of research and led to the development of orexin receptor antagonist drugs like suvorexant (Belsomra) for insomnia. Published in Cell — one of the highest-impact journals in biology.

The orexin discovery reshaped our understanding of how the brain controls appetite, sleep, and arousal. Within a few years, researchers found that narcolepsy — a disorder of uncontrollable sleepiness — is caused by the destruction of orexin-producing neurons. This led to an entirely new drug class: orexin receptor antagonists for insomnia (suvorexant, lemborexant). Orexin agonists are now in development for narcolepsy treatment. This 1998 paper is where it all started.

This initial discovery study was conducted entirely in rats, so direct translation to human physiology wasn't established here (though it was later confirmed). The study focused on feeding behavior and didn't explore the many other functions orexins were later found to have, including sleep/wake regulation. The mechanism by which orexins stimulate feeding was not fully elucidated in this paper.