Serum Omega-3 Fatty Acids and Obesity-Comorbid Depression in US Adults: An Integrated Epidemiology and Network Pharmacology Study

Abstract

Omega-3 polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), possess anti-inflammatory properties, yet their association with obesity-depression comorbidity remains unclear. This study investigated the association among US adults and explored underlying mechanisms. We performed a cross-sectional analysis of 4,423 individuals participating in the National Health and Nutrition Examination Survey (NHANES) 2003–2004 & 2011–2014. Serum fatty acids were quantified by gas chromatography. Obesity was defined using anthropometric criteria, and depression was assessed using the PHQ-9 or antidepressant use. Multivariable logistic regression estimated odds ratios (ORs) per standard deviation (SD) increase in PUFA levels. Mechanistic explore through network pharmacology identified potential pathways, which were examined using correlation analyses with inflammatory indices. Higher omega-3 PUFA levels were associated with lower odds of central obesity comorbid depression in females (OR: 0.82, 95% CI: 0.69–0.96) and older adults (OR: 0.79, 95% CI: 0.64–0.97). DHA was significantly associated with lower odds of central obesity (OR: 0.83, 95% CI: 0.73–0.95), depressive symptoms (OR: 0.88, 95% CI: 0.77–1.00), and their comorbidity (OR: 0.85, 95% CI: 0.74–0.98), whereas no significant associations were found for EPA. Mechanistic exploration implicated DHA in TNF and IL-17 signaling pathways, supported by inverse correlations with monocyte-to-HDL ratio (r: −0.138, P < 0.001) and lymphocyte-to-HDL ratio (r: −0.108, P < 0.001). In conclusion, serum DHA is inversely associated with obesity-depression comorbidity, with potential involvement of anti-inflammatory pathways. These findings underscore the potential of DHA for the management of obesity comorbid depression and the need for further interventional trials.