How the Hunger Hormone Ghrelin Was Discovered: A 26-Year Journey From Synthetic Peptides to a Stomach Hormone | Research

The takeaway

The discovery of ghrelin in 1999 was the culmination of 26 years of research on synthetic growth hormone-releasing peptides, and it revealed a hormone system that controls not just growth hormone but also hunger, metabolism, and inflammation.

26 years
From the discovery of synthetic GHRPs in 1976 to the isolation and identification of their natural counterpart, ghrelin, from the stomach in 1999

What the researchers found

This historical review traces the 26-year journey from the first synthetic growth hormone-releasing peptides (GHRPs) in 1976 to the isolation of ghrelin from the stomach in 1999. Key milestones: somatostatin isolation (1973), discovery of unnatural GHRPs (1976), GHRH isolation (1982), the hypothesis that GHRPs reflect a new, undiscovered hormone (1984), demonstration of GHRP+GHRH synergy in humans (1990), discovery and cloning of the GHS/GHRP receptor (1996–1998), and finally ghrelin's isolation and identification by Kojima and Kangawa (1999).

A critical insight was that GHRPs release more growth hormone than GHRH when given intravenously in humans, but the reverse is true in laboratory cell cultures — suggesting GHRPs act on both the hypothalamus and pituitary, not just the pituitary. GHRPs are active by multiple routes (IV, subcutaneous, oral, intranasal), and ghrelin turned out to be pleiotropic, affecting not just growth hormone but also appetite, metabolism, cardiovascular function, immunity, and inflammation.

Why it matters

Ghrelin's discovery fundamentally changed our understanding of growth hormone regulation and appetite control. Written by Cyril Bowers — the researcher who discovered GHRPs and drove much of this field for decades — this review provides a first-person account of how synthetic peptides led to the discovery of one of the body's most important hormones. The ghrelin system is now central to research on obesity, cachexia, growth disorders, and metabolic disease.

The numbers in context

1976: first GHRPs discovered · 1999: ghrelin isolated from stomach · GHRP+GHRH synergy demonstrated in humans · GHRPs active via IV, SC, oral, intranasal routes · Ghrelin system conserved since zebrafish evolution

How the study worked

Historical narrative review written by one of the field's pioneers, chronicling key experiments, discoveries, and conceptual developments from 1973 to the present across basic science, animal studies, and clinical research.

Who was studied

Historical review covering research in cell cultures, animal models (rats, zebrafish), and human clinical studies spanning children, adults, and elderly subjects

What this study cannot tell us

This is a historical narrative from the perspective of one of the field's principal investigators. While comprehensive, it naturally emphasizes the author's contributions and perspective. It is not a systematic review and does not critically appraise the quality of individual studies.

How to read the evidence

This is a historical review written by one of the field's founders. It provides authoritative first-person context for major discoveries but is not a systematic review or primary research study.

When this study was published

Published in 2012. While over a decade old, this remains a definitive historical account of ghrelin's discovery. The ghrelin field has continued to expand, but the historical narrative it presents is permanent.

The bigger picture

Ghrelin's discovery reshaped multiple fields of medicine. It explained how the body regulates growth hormone pulses, revealed the molecular basis of hunger signaling, and opened new therapeutic avenues for conditions from growth disorders to cancer-related wasting (cachexia). The GHS receptor became a major drug target, spawning clinical development of ghrelin agonists (like anamorelin for cachexia) and growth hormone secretagogues (like ibutamoren/MK-677).

Questions still open

Could ghrelin-based therapies be developed for conditions beyond growth hormone deficiency, such as sarcopenia or neurodegenerative disease?
Why does ghrelin's primary production site turn out to be the stomach rather than the brain, given its central role in growth hormone regulation?
How can the pleiotropic effects of ghrelin be harnessed therapeutically while minimizing unwanted side effects like excessive hunger?

Common questions

What is ghrelin and why was its discovery important?

Ghrelin is a peptide hormone primarily produced in the stomach that stimulates growth hormone release and triggers hunger. Its discovery in 1999 was important because it revealed a previously unknown hormonal system that connects appetite, growth, metabolism, and multiple organ systems — fundamentally changing our understanding of how the body regulates these processes.

What are GHRPs and how did they lead to ghrelin's discovery?

GHRPs (growth hormone-releasing peptides) are synthetic peptides created in 1976 that powerfully stimulate growth hormone release through a mechanism different from the known hormone GHRH. Because they worked through an unknown receptor, researchers spent decades searching for the natural hormone that normally activates it — ultimately finding ghrelin in the stomach in 1999.

Read the original research

History to the discovery of ghrelin.

Methods in enzymology, 514, 3-32

View on PubMed ↗Publisher’s paper ↗

Citation

Bowers, Cyril Y. (2012). History to the discovery of ghrelin.. Methods in enzymology, 514, 3-32. https://doi.org/10.1016/B978-0-12-381272-8.00001-5