Central ghrelin infusion increases aggression in male mice through a serotonin-dependent mechanism, and a human genetic variant in the ghrelin gene is associated with aggression in young men who drink heavily.
784 young men studiedHuman genetic component found the Leu72Leu ghrelin gene variant associated with greater aggression specifically in those with hazardous alcohol consumption
What the researchers found
Central (intracerebroventricular) ghrelin infusion increased aggression in male mice using the resident-intruder test, while systemic ghrelin injection did not — indicating the effect requires direct brain action. Blocking the ghrelin receptor (GHSR-1A) with JMV2959 reduced aggression, and this anti-aggressive effect was abolished when brain serotonin was depleted. Ex vivo biochemical data pointed to serotonin in the amygdala as the key mediator. In a human genetic study of 784 young men, the Leu72Leu genotype of the pre-pro-ghrelin gene was associated with greater aggression specifically in those with hazardous alcohol use.
Why it matters
Aggression is a major public health concern, especially alcohol-fueled violence. Understanding the biological mechanisms behind aggressive behavior could lead to better prevention and treatment strategies. This study identifies the central ghrelin pathway — a peptide system already targeted by drugs for other conditions — as a modulator of aggression through serotonin signaling, opening potential pharmacological approaches to managing pathological aggression.
How the study worked
The study combined mouse behavioral experiments with human genetic analysis. In mice, central and peripheral ghrelin administration was tested alongside the GHSR-1A antagonist JMV2959 in the resident-intruder aggression paradigm. Serotonin depletion experiments tested whether the ghrelin-aggression link depended on serotonergic signaling. Ex vivo analysis measured serotonin, dopamine, and noradrenaline in the amygdala. The human component was a genetic association study in 784 young men from the general population, examining pre-pro-ghrelin gene variants in relation to self-reported antisocial behaviors and alcohol use.
What this study cannot tell us
The mouse experiments used central ghrelin infusion, which doesn't reflect natural ghrelin signaling dynamics. The human genetic study was cross-sectional and observational, so it cannot prove the ghrelin variant causes aggression. Only males were studied in both the mouse and human components, limiting generalizability to females. The human aggression measure relied on self-reported antisocial behaviors rather than direct behavioral observation. The genetic association would need replication in independent cohorts.
How to read the evidence
This is a translational study combining preclinical mouse experiments (behavioral pharmacology with mechanistic follow-up) and a human genetic association study. The multi-level approach strengthens the overall evidence, though the human component is observational and the genetic association requires replication.
When this study was published
Published in 2019, this study reflects a growing interest in ghrelin's non-metabolic functions and remains relevant to ongoing research on peptide hormones and behavior.
The bigger picture
Ghrelin is increasingly recognized as far more than a hunger signal — it influences reward, mood, addiction, and now aggression. This study adds aggression to ghrelin's behavioral portfolio and connects it to serotonin, the neurotransmitter most classically associated with aggression and impulse control. The alcohol-aggression genetic finding is particularly relevant given that alcohol is the substance most commonly linked to violent behavior, and ghrelin levels are known to be altered in alcohol use disorders.
Questions still open
- Could ghrelin receptor antagonists be developed as treatments for pathological aggression or alcohol-related violence?
- Does the ghrelin-aggression link extend to females, or is it specific to male biology?
- Do people with eating disorders or conditions that alter ghrelin levels show changes in aggressive behavior?
Common questions
How could the hunger hormone ghrelin be linked to aggression?
What does the human genetic finding mean for understanding alcohol-related violence?
Read the original research
Ghrelin and aggressive behaviours-Evidence from preclinical and human genetic studies.
Psychoneuroendocrinology, 104, 80-88
Citation
Vestlund, Jesper; Winsa-Jörnulf, Julia; Hovey, Daniel; Lundström, Sebastian; Lichtenstein, Paul; Anckarsäter, Henrik; Studer, Erik; Suchankova, Petra; Westberg, Lars; Jerlhag, Elisabet. (2019). Ghrelin and aggressive behaviours-Evidence from preclinical and human genetic studies.. Psychoneuroendocrinology, 104, 80-88. https://doi.org/10.1016/j.psyneuen.2019.02.020