Synthetic Ghrelin Drugs Boost Appetite but Unexpectedly Reduce Reward-Seeking in Rodents
Anamorelin and HM01 increased food intake but paradoxically reduced food reward behavior compared to ghrelin, demonstrating biased signaling at the ghrelin receptor.
Quick Facts
What This Study Found
Anamorelin and HM01 are synthetic ghrelin receptor (GHSR-1a) agonists with clinical potential for appetite stimulation. In cellular assays, they showed biased signaling, activating some downstream pathways (calcium mobilization, IP-one) but differing from ghrelin in internalization and beta-arrestin recruitment patterns.
In rodent feeding studies, both drugs increased food intake, confirming appetite-stimulating effects. However, in reward paradigms (tests measuring motivation to work for food or pleasurable substances), both drugs paradoxically reduced reward-seeking behavior.
Brain c-Fos immunostaining (a marker of neuron activation) revealed divergent activation of central reward circuitry compared to what would be expected from natural ghrelin.
The key insight: biased signaling matters. These drugs activate the ghrelin receptor differently than natural ghrelin, leading to different behavioral outcomes. For future ghrelin-based therapies, understanding exactly which signaling pathways a drug activates, and whether it reaches reward areas of the brain, will determine success or failure.
Key Numbers
Anamorelin and HM01 vs ghrelin; increased food intake; reduced reward behavior; divergent c-Fos brain activation; biased signaling confirmed
How They Did This
In vitro cellular assays: calcium mobilization, IP-one accumulation, receptor internalization, and beta-arrestin recruitment comparing anamorelin, HM01, and ghrelin. In vivo rodent studies: food intake measurements, reward-motivated behavior paradigms, and c-Fos brain mapping to identify activated brain regions.
Why This Research Matters
Ghrelin receptor agonists are being developed for cancer-related wasting (cachexia) and appetite disorders. This study warns that biased signaling can produce unexpected behavioral effects. A drug that increases appetite but reduces food reward motivation may work for cachexia but could have unintended consequences. Understanding signaling bias is essential for designing the right drug for the right condition.
The Bigger Picture
Biased signaling is a growing field in pharmacology. This study shows that ghrelin receptor drugs can separate appetite stimulation from reward/pleasure effects. This distinction matters for treating cachexia without potential addictive properties, and warns against assuming drugs mimic their natural hormone counterparts.
What This Study Doesn't Tell Us
Rodent reward behavior may not translate to human experience. The specific reward paradigms chosen may not capture all aspects of food motivation. The paradoxical reduction in reward seeking could reflect the specific behavioral tests used rather than a general effect. Dosing and biodistribution differences between drugs complicate comparison.
Questions This Raises
- ?Is the reduced reward-seeking behavior clinically beneficial or problematic?
- ?Would patients report reduced enjoyment of food despite eating more?
- ?Can biased signaling be engineered to select specific therapeutic effects?
Trust & Context
- Key Stat:
- Biased signaling synthetic ghrelin drugs boost appetite but reduce food reward — opposite to natural ghrelin's reward-enhancing effect
- Evidence Grade:
- Moderate evidence from combined in vitro and rodent behavioral studies. The biased signaling is clearly demonstrated but human behavioral translation is uncertain.
- Study Age:
- Published in 2020. Anamorelin is approved in Japan for cancer cachexia. Biased agonism research continues to influence drug design.
- Original Title:
- Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents.
- Published In:
- Neuropharmacology, 168, 108011 (2020)
- Authors:
- Howick, Ken(2), Chruscicka, Barbara, Felice, Daniela, Ramirez, Valerie T, van Leuven, Lucas, Pietra, Claudio, Cryan, John F, Griffin, Brendan T, Schellekens, Harriët
- Database ID:
- RPEP-04860
Evidence Hierarchy
Frequently Asked Questions
What is biased signaling?
A receptor can activate multiple pathways inside a cell. A drug with biased signaling only activates some of these, not all. This means it produces some effects of the natural hormone but not others.
Why does this matter for cancer patients with cachexia?
Cachexia drugs need to increase food intake. If they also reduce food enjoyment (reward), patients may eat more but enjoy it less. Understanding this tradeoff helps design better appetite medications.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-04860APA
Howick, Ken; Chruscicka, Barbara; Felice, Daniela; Ramirez, Valerie T; van Leuven, Lucas; Pietra, Claudio; Cryan, John F; Griffin, Brendan T; Schellekens, Harriët. (2020). Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents.. Neuropharmacology, 168, 108011. https://doi.org/10.1016/j.neuropharm.2020.108011
MLA
Howick, Ken, et al. "Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents.." Neuropharmacology, 2020. https://doi.org/10.1016/j.neuropharm.2020.108011
RethinkPeptides
RethinkPeptides Research Database. "Behavioural characterization of ghrelin ligands, anamorelin ..." RPEP-04860. Retrieved from https://rethinkpeptides.com/research/howick-2020-behavioural-characterization-of-ghrelin
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.