Overweight individuals with reduced insulin sensitivity often have mild to moderate hypertriglyceridemia. To investigate the role of apolipoprotein (apo)C-III metabolism in the etiology of hypertriglyceridemia in these individuals, we investigated 10 male subjects with different body weights (body mass index, 24-34 kg/m2) and insulin sensitivity (homeostasis model assessment, 4.7-35.0). Total plasma and very-low-density lipoprotein (VLDL) apoC-III kinetics, as well as VLDL triglyceride (TG) and VLDL apoB kinetics, were measured with iv injected stable isotopes. The apoC-III, TG, and apoB levels in VLDL ranged from 2.9-18.2 mg/dl, 0.49-2.89 mmol/ liter, and 6.7-29.3 mg/dl, respectively. Mean production rates (PRs) were: VLDL apoC-III, 20.2 ± 4.1 μmol/d (range, 8.0-44.8); VLDL TG, 26.9 ± 4.6 mmol/d (range, 10.2-51.1); and VLDL apoB, 4.4 ± 0.8 μmol/d (range, 1.5-9.1). VLDL apoC-III PRs were significantly correlated with body mass index, homeostasis model assessment, and plasma TG (r = 0.66, P < 0.05; r = 0.80, P < 0.01; r = 0.95, P < 0.001, respectively). Similar correlations were found for plasma apoC-III PRs (r = 0.70, P < 0.05; r = 0.67, P < 0.05; r = 0.80, P < 0.01, respectively). Fractional catabolic rates (FCRs) were not significantly related to metabolic variables. VLDL TG levels were strongly related to VLDL apoC-III levels (r = 0.99, P < 0.001) and VLDL apoC-III PRs (r = 0.94, P < 0.001). VLDL apoC-III levels were more strongly correlated with VLDL TG PRs (r = 0.81, P < 0.01) than with VLDL TG FCRs or VLDL apoB FCRs (r = -0.53, P = 0.12; r = -0.37, P = 0.29). These results suggest that increased hepatic production of VLDL apoC-III is characteristic of subjects with higher body weights and lower levels of insulin sensitivity and is strongly related to the plasma concentration and level of production of VLDL TG.