The Role of Morning Plasma Cortisol in Obesity: A Bidirectional Mendelian Randomization Study

Abstract

Abstract Context Cortisol, an important hormone regulated by the hypothalamic-pituitary-adrenal axis, is associated with obesity. However, it is unclear whether the relationship between cortisol and obesity is causal or could be explained by reverse causality. Objective This work aims to assess the role of morning plasma cortisol in clinical classes of obesity. Methods In this bidirectional, 2-sample mendelian randomization (MR) study, cortisol-associated genetic variants were obtained from the CORtisol NETwork consortium (n = 12 597). The primary outcomes were obesity class I (body mass index [BMI] ≥ 30), class II (BMI ≥ 35), and class III (BMI ≥ 40). The inverse variance weighting method was used as the main analysis, with weighted median, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) as sensitivity analyses. Conversely, genetic variants predicting clinical classes of obesity were applied to the cortisol genome-wide association study. Results Genetically predicted cortisol was associated with reduced risk of obesity class I (OR = 0.905; 95% CI, 0.865-0.946; P < .001). Evidence from bidirectional MR showed that obesity class II and class III were associated with lower cortisol levels ([class II-cortisol OR = 0.953; 95% CI, 0.923-0.983; P = .002]; [class III-cortisol OR = 0.955; 95% CI, 0.942-0.967; P < .001]), indicating reverse causality between cortisol and obesity. Conclusion This study demonstrates that cortisol is negatively associated with obesity and vice versa. Together, these findings suggest that blunted morning plasma cortisol secretion may be responsible for severe obesity. Regulating morning plasma cortisol secretion might be a prevention measure for obese people.