Ghrelin rises in depression despite obesity’s usual appetite-hormone suppression

By Hugo Francisco de SouzaReviewed by Susha Cheriyedath, M.Sc.May 27 2026

A new study finds elevated active and deacylated ghrelin in unmedicated patients with both major depression and obesity, pointing to a stress-linked hormonal signal that could reshape how researchers study depression in metabolically complex patients.

Study: Levels of acylated and deacylated ghrelin are elevated in unmedicated patients with major depressive disorder and obesity: a cross-sectional study. Image Credit: Overearth / Shutterstock

In a recent study published in the journal Scientific Reports, researchers conducted a cross-sectional study to examine whether ghrelin, an appetite-regulating hormone, is involved in the co-occurrence of major depressive disorder (MDD) and obesity. The study specifically measured circulating ghrelin in unmedicated patients experiencing both MDD and obesity, and compared these findings against those from a non-depressed control group also living with obesity.

Study findings revealed that individuals with MDD have significantly higher levels of both active and deacylated ghrelin, suggesting that a unique form of neuroendocrine dysregulation is associated with clinical depression in obese individuals.

Background

Major depressive disorder (MDD) is a globally debilitating condition characterized by persistent low mood and loss of interest in activities that lasts for at least two weeks. The condition is estimated to impact between 7.5% and 34% of all individuals, and is often found to co-occur alongside obesity, with each disorder appearing to heighten a patient’s risk for developing the other.

While scientists have long suspected that shared physiological disruptions link the two conditions, empirical evidence for mechanisms that simultaneously modulate obesity and MDD remains lacking.

Recent scientific interest has focused on the hormone ghrelin, a 28-amino-acid peptide best known for its role in triggering hunger during fasting. Produced primarily by neuroendocrine cells in the stomach, recent research indicates that the hormone can cross the blood-brain barrier (BBB), where it is observed to influence dopamine pathways, thereby actively shaping the neurological processing of subjective stress and reward.

Unfortunately, previous literature investigating ghrelin's role in depression has produced conflicting results, potentially because most prior research has focused on total ghrelin rather than its two biologically distinct forms: acylated ghrelin (the active form) and deacylated ghrelin (the more abundant, lower-potency form with distinct biological effects).

About the study

The present study addresses this knowledge gap by conducting a cross-sectional study in Warsaw, Poland, to investigate whether ghrelin levels differ in patients with co-occurring major depressive disorder (MDD) and obesity. The study compared data from 31 unmedicated adults experiencing MDD and obesity with 31 non-depressed control subjects who also had obesity, thereby reducing the confounding influence of obesity when assessing depression-associated hormonal differences.

Notably, patients in the MDD group were screened to ensure that only those entirely free of psychiatric medications for at least 12 months were included in the final analysis dataset, thereby reducing medication-related confounding.

Study data included participants’ sociodemographic and medical histories, including body mass index (BMI). Subsequently, the study assessed patients’ depressive symptoms using the Patient Health Questionnaire-9 (PHQ-9), and formal MDD diagnoses were confirmed through the structured Mini-International Neuropsychiatric Interview (M.I.N.I.).

Participants’ blood samples (for ghrelin estimation assays) were collected after an overnight fast of at least 10 hours. Since ghrelin is known to rapidly degrade outside the body, a protease inhibitor was used to prevent its breakdown. The blood was then chilled in a pre-cooled centrifuge and stored at -80 degrees Celsius.

Enzyme-linked immunosorbent assay (ELISA) kits were used to estimate ghrelin concentrations (acylated and deacylated quantified separately).

Study findings

Study findings revealed that participants with MDD exhibited significantly higher circulating levels of both ghrelin fractions compared to their non-depressed counterparts. Initial unadjusted statistical tests showed higher concentrations for both acylated (p < 0.001) and deacylated (p = 0.007) ghrelin.

Multivariable general linear models, adjusted for participants’ sex, age, and BMI, corroborated these findings, further revealing that MDD was an independent predictor of higher hormone levels. The analyses found that the adjusted mean log-transformed acylated ghrelin concentration was 3.50 in the depressed group versus 2.71 in the control group (p < 0.001), highlighting a statistical difference between the cohorts.

Similarly, the adjusted mean log-transformed deacylated ghrelin level was 4.51 in MDD patients compared to 4.07 in controls (p = 0.011). In both cases, the results showed that the effect size was stronger for the biologically active, acylated form of the hormone.

Interestingly, the ratio of acylated to deacylated ghrelin did not differ significantly between the groups (p = 0.072), suggesting that MDD is associated with a systemic increase in overall ghrelin secretion rather than a selective shift toward acylation, although the authors noted that this trend-level finding was underpowered and requires replication in larger samples.

Conclusions

The present study is one of the few to separately assess acylated and deacylated ghrelin in antidepressant-free patients with MDD and obesity. The fact that these ghrelin fractions remained significantly elevated in obese patients with MDD suggests that depression may be associated with ghrelin-system dysregulation even within a metabolic state usually linked to lower ghrelin levels.

The authors hypothesize that this hormone surge might be the body's compensatory neuroendocrine response to the chronic stress tied to depressive episodes. However, because the study was cross-sectional, it cannot determine whether elevated ghrelin contributes to MDD, results from chronic stress, or reflects shared neuroendocrine dysregulation. Future longitudinal studies with larger sample sizes will be needed to verify if ghrelin could serve as a reliable biological marker for depression in patients with complex metabolic profiles.

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