Role of Circulating Lipids in Mediating the Pro-Diabetic Effect of Obesity

Background/Objectives: Obesity is a major risk factor for diabetes, but the underlying mechanisms remain incompletely understood. Obesity is associated with alterations in circulating lipids. This study aimed to determine whether, and to what extent, circulating lipids mediate the pro-diabetic effect of obesity. Methods: We analyzed data from 26,627 US adults. Mediation analysis was performed using the PROCESS Version 4.3 Macro for SPSS. Parallel mediation analysis included total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides as simultaneous mediators. Low-density lipoprotein (LDL) cholesterol was excluded from the parallel model due to collinearity with total cho-lesterol and was assessed separately using simple mediation analysis adjusted for con-founders. Results: After adjustment for tested confounders, parallel mediation analysis showed that increases in triglycerides and reductions in HDL cholesterol mediated 24.0% (indirect effect coefficient = 0.23; 95% CI: 0.20–0.26; p < 0.05) and 3.8% (indirect effect coef-ficient = 0.04; 95% CI: 0.01–0.06; p < 0.05) of the pro-diabetic effect of obesity, respectively. An increase in total cholesterol negatively mediated the effect by 2.3% (indirect effect coef-ficient = -0.02; 95% CI: -0.03 to -0.01; p < 0.05). Simple mediation analysis indicated that LDL cholesterol was not a significant mediator. Conclusions: Triglycerides are the most influential circulating lipid in mediating the pro-diabetic effect of obesity, accounting for 24% of the total effect. Targeting triglyceride levels may represent an underrecognized therapeutic strategy to reduce obesity-related diabetes risk.