Interplay of neuropeptide Y, metabolic dysfunction, and inflammation in cognitive impairment of major depressive disorder: a sex-stratified study

Abstract

Abstract Background Major depressive disorder (MDD) is associated with metabolic disturbances (elevated TyG index), peripheral inflammation (IL-6, TNF-α, CRP), and cognitive deficits. Serum NPY levels vary by sex and reproductive aging, influencing appetite changes in MDD. However, the interplay between NPY, metabolic dysfunction, inflammation, and cognition stratified by sex and menopausal status remains unexplored. This study investigated whether NPY mediates the TyG index–cognitive impairment relationship, moderated by inflammation and sex/reproductive status. Methods In a cross-sectional study (February 2021–September 2024), 300 MDD patients (100 males, 100 premenopausal females, 100 postmenopausal females) and 150 age- and BMI-matched healthy controls were recruited. Assessments included TyG index, serum NPY (ELISA), inflammatory markers, MoCA, VAS appetite, and HAMD-17. Analysis used Pearson correlations, multiple linear regression, moderated mediation (PROCESS Model 58), and ROC curves for a combined biomarker panel (TyG + NPY + IL-6 + TNF-α). Results MDD patients showed higher TyG, NPY (especially premenopausal females), inflammation, and lower MoCA scores than controls (all P < 0.001). NPY positively correlated with TyG and VAS appetite ( r = 0.43–0.52, P < 0.001) and negatively with MoCA ( r = − 0.35 to − 0.46, P < 0.001), strongest in premenopausal females. Inflammation partially mediated NPY–MoCA (indirect effect = − 0.046, 95% CI [− 0.076, − 0.021], 39.32% of total). NPY and inflammation jointly mediated TyG–MoCA (joint indirect effect = − 0.118, 95% CI [− 0.189, − 0.052], 36.88% of total), moderated by sex/reproductive status (index = − 0.148, 95% CI [− 0.238, − 0.058]). Subgroup indirect effects peaked in premenopausal females (42.37%, − 0.136 [− 0.218, − 0.059]). The integrated panel outperformed TyG alone (AUC = 0.869 [0.829, 0.909] vs. 0.748 [0.695, 0.801]; DeLong Z = 3.92, P < 0.001). Conclusion This study reveals a sex-specific pathway linking NPY, metabolic dysfunction, and inflammation to cognitive decline in MDD. The integrated biomarker panel offers superior diagnostic utility. Longitudinal studies are warranted for causality and intervention potential. Clinical trial number Not applicable.