Despite ghrelin being the only known hunger-stimulating hormone, developing drugs that target its receptor for appetite control has been hampered by receptor complexity, widespread expression, and difficulty crossing the blood-brain barrier.
No approved ghrelin-targeting appetite drugDespite ghrelin being identified as the hunger hormone over 20 years ago, receptor complexity and drug delivery barriers have prevented successful therapeutic development
What the researchers found
Ghrelin's central brain signaling is critical for its effects on appetite, body weight, and food reward. However, multiple factors have prevented successful drug development: GHSR-1a receptor internalization and heterodimerization create complex pharmacology, biased ligand interactions produce unpredictable effects, compensatory neuroendocrine outputs counteract drug effects, and the receptor's ubiquitous expression makes it impossible to target appetite without affecting peripheral ghrelin functions. Improving blood-brain barrier penetration of ghrelin ligands, particularly to reach mesolimbic reward circuitry, is identified as a key priority.
Why it matters
Understanding why ghrelin-targeting drugs haven't succeeded explains a major gap in the obesity and cachexia treatment landscape. While GLP-1 drugs have conquered the satiety side of appetite, the hunger side — driven by ghrelin — remains pharmacologically intractable. Solving the ghrelin drug delivery and receptor selectivity challenges could complement existing GLP-1 therapies and address conditions where appetite stimulation is needed, such as cancer cachexia and anorexia in the elderly.
How the study worked
Narrative review of the ghrelin system biology, receptor pharmacology, and therapeutic development efforts for appetite modulation, covering both preclinical and clinical evidence.
What this study cannot tell us
As a 2017 review, it predates some recent advances in ghrelin pharmacology and drug delivery. The review covers a wide scope, which limits depth on individual drug candidates. The emphasis on challenges may understate progress in understanding ghrelin biology. Some therapeutic leads mentioned may have since advanced or been abandoned.
How to read the evidence
This is a narrative review covering preclinical and clinical evidence on ghrelin pharmacology and drug development. It provides an expert synthesis of the field's challenges but does not include systematic methodology or new experimental data.
When this study was published
Published in 2017, this review captures the challenges that persisted in ghrelin drug development at that time. Many of these challenges remain relevant, though the field has continued to advance with new approaches to receptor pharmacology and drug delivery.
The bigger picture
The ghrelin story illustrates a common challenge in peptide drug development: understanding a peptide's biology is far easier than successfully drugging its receptor. While GLP-1 drugs succeeded in part because the receptor pharmacology was simpler, ghrelin's receptor system is more complex — heterodimerizing, internalizing, and exhibiting constitutive activity. The lessons learned from ghrelin drug development failures inform broader peptide therapeutic research and highlight the importance of brain-penetrant peptide drug design.
Questions still open
- Could nanoparticle or peptide-conjugate delivery systems improve ghrelin ligand penetration across the blood-brain barrier?
- Would biased ghrelin receptor agonists that selectively activate appetite-related signaling pathways succeed where non-selective agonists failed?
- Could combining ghrelin-targeting and GLP-1-targeting drugs produce superior weight management outcomes?
Common questions
What is ghrelin and why is it called the hunger hormone?
Why can't we just block ghrelin to treat obesity?
Read the original research
From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation.
International journal of molecular sciences, 18(2)
Citation
Howick, Ken; Griffin, Brendan T; Cryan, John F; Schellekens, Harriët. (2017). From Belly to Brain: Targeting the Ghrelin Receptor in Appetite and Food Intake Regulation.. International journal of molecular sciences, 18(2). https://doi.org/10.3390/ijms18020273