HIV protease inhibitors block adipogenesis and increase lipolysis in vitro

AIDS therapies employing HIV protease inhibitors (PIs) are associated with changes in fat metabolism. However, the cellular mechanisms affected by PIs are not clear. Thus, the affects of PIs on adipocyte differentiation were examined in vitro using C3H10T1/2 stem cells. In these cells the PIs, nelfi navir, saquinavir, and ritonavir, reduced triglyceride accumulation, lipoge nesis, and expression of the adipose markers, aP2 and LPL. Histological ana lysis revealed nelfinavir, saquinavir and ritonavir treatment decreased oil red O-staining of cytoplasmic fat droplets. Inhibition occurred in the pre sence of the RXR agonist LGD1069, indicating the inhibitory effects were no t due to an absence of RXR ligand. Moreover, these three Pls increased acut e lipolysis in adipocytes. In contrast, two HIV PIs, amprenavir and indinav ir, had little effect on lipolysis, lipogenesis, or expression of aP2 and L PL. Although, saquinavir, inhibited ligand-binding to PPAR gamma with an IC 50, of 12.7 +/- 3.2 mu M, none of the other PIs bound to the nuclear recept ors RXR alpha or PPAR gamma, (IC(50)s> 20 mu M), suggesting that inhibition of adipogenesis is not due to antagonism of ligand binding to RXR alpha or PPAR gamma. Taken together, the results suggest that some, but not all, PI s block adipogenesis and stimulate fat catabolism in vitro and this may con tribute to the effects of PIs on metabolism in the clinic. (C) 2000 Elsevie r Science B.V. All rights reserved.