The HIV protease inhibitor nelfinavir induces insulin resistance and increases basal lipolysis in 3T3-L1 adipocytes

HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been lin ked to the development of a metabolic syndrome in which adipocyte insulin r esistance appears to play a major role. In this study, we assessed the effe ct of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 a dipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-s timulated glucose uptake and activation of basal lipolysis. Impaired insuli n stimulation of glucose up take occurred at nelfinavir concentrations >10 mu mol/l (EC50 = 20 mu mol/l) and could be attributed to impaired GLUT4 tra nslocation. Basal glycerol and free fatty acid (FFA) release were significa ntly enhanced with as low as 5 mu mol/l nelfinavir, displaying fivefold sti mulation of FFA release at 10 mu mol/l. Yet, the antilipolytic action of in sulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of p rotein kinase B Ser 473 phosphorylation with preserved insulin receptor sub strate tyrosine phosphorylation and decreased expression of the lipolysis r egulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partl y protected the cells from the increase in basal lipoysis, but it had no ef fect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance an d activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte meta bolism in treated HIV patients.