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

The takeaway

Scientists discovered orexin-A and orexin-B, two entirely new brain peptides produced in the hypothalamus that stimulate appetite and are upregulated by fasting.

2 entirely new peptides
Orexin-A and orexin-B were a completely novel peptide family with no resemblance to any known regulatory peptides

What the researchers found

This landmark study identified two entirely new neuropeptides — orexin-A and orexin-B — both produced from the same precursor protein in the hypothalamus. These peptides bind to and activate two closely related G protein-coupled receptors that had previously been "orphan" receptors (receptors with no known ligand).

Orexin-A and orexin-B have no structural similarity to any previously known regulatory peptides, making them a completely novel peptide family. They are produced by neurons in and around the lateral and posterior hypothalamus of rat brains. When injected into the brain, both peptides stimulated food consumption. Furthermore, fasting caused an increase in prepro-orexin mRNA, indicating these peptides are part of the body's natural feedback system for regulating hunger and feeding behavior.

Why it matters

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 numbers in context

2 novel neuropeptides identified · 2 orphan GPCRs matched · Orexin-A and orexin-B from same precursor · Lateral/posterior hypothalamus localization · Fasting upregulates prepro-orexin mRNA

How the study worked

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.

Who was studied

Wistar rats (in vivo feeding studies); CHO cells (receptor activation assays)

What this study cannot tell us

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.

How to read the evidence

This is a landmark original research paper published in Cell, one of the most prestigious scientific journals. It represents the foundational discovery of the entire orexin/hypocretin field. The findings have been replicated and expanded upon thousands of times since 1998.

When this study was published

Published in 1998. This is 28 years old but remains one of the most cited papers in neuropeptide research. It is the original discovery paper for orexins — historical and foundational, not outdated.

The bigger picture

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.

Questions still open

Do orexins play the same appetite-stimulating role in humans as in rats?
What other functions might orexin-producing neurons serve beyond feeding behavior?
Could orexin system dysfunction contribute to obesity or metabolic disorders?

Common questions

What are orexins and why were they such an important discovery?

Orexins (also called hypocretins) are two brain peptides discovered in 1998 that are made by a small group of neurons in the hypothalamus. They were originally found to stimulate appetite, but turned out to also control wakefulness, arousal, and reward. The discovery that loss of orexin neurons causes narcolepsy, and the subsequent development of orexin-targeting sleep medications, made this one of the most impactful peptide discoveries in modern neuroscience.

How did this discovery lead to sleep medications?

After orexins were discovered to promote wakefulness, researchers found that blocking orexin receptors could help people fall asleep. This led to the development of orexin receptor antagonists — drugs like suvorexant (Belsomra) and lemborexant (Dayvigo) — which are now FDA-approved for treating insomnia. Conversely, orexin agonists are being developed to treat narcolepsy by replacing the missing orexin signal.

Read the original research

Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.

Cell, 92(4), 573-85

View on PubMed ↗

Citation

Sakurai, T; Amemiya, A; Ishii, M; Matsuzaki, I; Chemelli, R M; Tanaka, H; Williams, S C; Richardson, J A; Kozlowski, G P; Wilson, S; Arch, J R; Buckingham, R E; Haynes, A C; Carr, S A; Annan, R S; McNulty, D E; Liu, W S; Terrett, J A; Elshourbagy, N A; Bergsma, D J; Yanagisawa, M. (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior.. Cell, 92(4), 573-85.