HIV protease inhibitors block human preadipocyte differentiation, but not via the PPAR gamma/RXR heterodimer

A recent prospective clinical study has shown that antiviral therapy with H IV protease inhibitors (PIs) is associated with a syndrome of peripheral fa t wasting (lipodystrophy) and disordered glucose and lipid metabolism (Carr et al. 1999). We have studied the effects of indinavir and saquinavir, two HIV protease inhibitors, on cultured primary human preadipocytes and repor t that these compounds inhibit their differentiation. However, we find that these agents do not inhibit either transcriptional activation or adipocyte P2 gene induction by the PPAR gamma/RXR nuclear receptor heterodimer. Toge ther, our findings suggest that impaired adipogenesis is the basis of PI-as sociated lipodystrophy, but that this occurs via a PPAR gamma/RXR-independe nt mechanism.