Anamorelin and HM01 increased food intake but paradoxically reduced food reward behavior compared to ghrelin, demonstrating biased signaling at the ghrelin receptor.
Biased signalingsynthetic ghrelin drugs boost appetite but reduce food reward — opposite to natural ghrelin's reward-enhancing effect
What the researchers 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.
Why it 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 numbers in context
Anamorelin and HM01 vs ghrelin; increased food intake; reduced reward behavior; divergent c-Fos brain activation; biased signaling confirmed
How the study worked
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.
Who was studied
Rodents (food intake and reward behavior); cell-based signaling assays
What this study cannot 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.
How to read the evidence
Moderate evidence from combined in vitro and rodent behavioral studies. The biased signaling is clearly demonstrated but human behavioral translation is uncertain.
When this study was published
Published in 2020. Anamorelin is approved in Japan for cancer cachexia. Biased agonism research continues to influence drug design.
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.
Questions still open
- 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?
Common questions
What is biased signaling?
Why does this matter for cancer patients with cachexia?
Read the original research
Behavioural characterization of ghrelin ligands, anamorelin and HM01: Appetite and reward-motivated effects in rodents.
Neuropharmacology, 168, 108011
Citation
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