The Mediating Role of Fasting Ghrelin Serum Levels in the Association between Obesity and Depressive Symptoms – a pre-registered analysis

Ghrelin, a hunger-related gut hormone, may contribute to higher risk of depression in obesity. Despite animal studies suggesting antidepressant effects of circulating ghrelin, human studies remain inconclusive. Therefore, we aimed to explore the association between obesity, ghrelin serum levels, and depressive symptoms in a large population-based cohort. Assessments of the LIFE-Adult cohort (n = 6037, 18-82 years) included self-administered questionnaires to evaluate depressive symptoms (CES-D and IDS-SR), anthropometric measurements to calculate body mass index (BMI), measurements of fasting ghrelin serum levels via radioimmunoassay (n = 1089), and 3T magnetic resonance imaging (MRI) to assess hippocampal volume (n = 1080). Statistical analyses were pre-registered (https://osf.io/y7sbx) and included linear regression that were controlled for physiological and psychosocial confounders. Accordingly, higher BMI predicted more frequent depressive symptoms (β = 2.033, p < 0.001) and lower fasting serum ghrelin (β = -0.622, p < 0.001). Ghrelin however did not correlate with depressive symptoms in obesity (n = 263, β = 0.123, p = 0.918). Exploratory analyses revealed links between ghrelin and eating-related depressive symptoms and that higher BMI was more strongly linked to depressive symptoms in females compared to males. No significant association between ghrelin and hippocampal volume was identified. In this pre-registered analysis in a large, well-characterized sample, ghrelin was not associated with the overall severity of depressive symptoms in participants living with obesity. Future studies using more specific ghrelin assessments and clinical samples could help to elucidate the relationship between ghrelin, obesity, and depression.