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PPAR ligands are important effectors of energy metabolism and can modify proteoglycan synthesis by vascular smooth muscle cells (VSMCs). Describing the cell biology of these important clinical agents is important for understanding their full clinical potential, including toxicity. Troglitazone (10 μM) and fenofibrate (30 μM) treatment of VSMCs reduces (35S)-sulphate incorporation into proteoglycans due to a reduction of glycosaminoglycan (GAG) chain length. Conversely, under physiological glucose conditions (5.5 mM), the same treatment increases (3H)-glucosamine incorporation into GAGs. This apparent paradox is the consequence of an increase in the intracellular (3H)-galactosamine specific activity from 48.2 ± 3.2 μCi/ μmol to 90.7 ± 11.0 μCi/ μmol (P < 0.001) and 57.1 ± 2.6 μCi/ μmol (P < 0.05) when VSMCs were treated with troglitazone and fenofibrate, respectively. The increased specific activity observed with troglitazone (10 μM) treatment correlates with a two-fold increase in glucose consumption, while fenofibrate (50 μM) treatment showed a modest (14.6%) increase in glucose consumption. We conclude that the sole use of glucosamine precursors to assess GAG biosynthesis results in misleading conclusions when assessing the effect of PPAR ligands on VSMC proteoglycan biosynthesis. [ABSTRACT FROM AUTHOR]