The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

The objective of our research was to investigate the effects of the protease inhibitors ritonavir, saquinavir, and indinavir on triglyceride synthesis, lipolysis, insulin binding, and signaling in differentiating 3T3 L1 pre-adipocytes. Saquinavir, ritonavir, and indinavir all stimulated triglyceride (TG) synthesis. Additionally, all concentrations of protease inhibitors employed (i.e., 0.1 muM to 10 muM) significantly decreased insulin-stimulated TG synthesis. No effects of any of the protease inhibitors were observed either on basal lipolysis or after stimulation of lipolysis with 100 nM noradrenaline. Specific I-125-insulin binding was observed to be decreased by exposure to all the protease inhibitors throughout the period of adipocyte phenotype development. This was mediated by indinavir through a receptor decrease and had no effect on receptor affinity. During differentiation with ritonavir (i.e., 1-11 days post addition of differentiating cocktail), insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation was ascertained (day 11) and found to be decreased in the ritonavir exposed cells when compared with control cells. The results reported herein demonstrate protease inhibitor effects on basal TG synthesis while exhibiting decreased insulin-stimulated TG synthesis at physiological concentrations of protease inhibitors. These effects may be subsequent to decreased insulin binding and/or IRS-1 tyrosine phosphorylation.