Inhibition of adipocyte differentiation by HIV protease inhibitors

Patients with AIDS who are receiving therapy with HIV protease inhibitors h ave been widely reported to be afflicted with a syndrome characterized by l ipodystrophy (fat redistribution favoring the accumulation of abdominal and cervical adipose tissue), hyperlipidemia, and insulin resistance. HIV prot ease inhibitors have been suggested to have a direct role in modulating adi pocyte differentiation. To address this hypothesis, several HIV protease in hibitors were studied for their ability to either augment or inhibit the di fferentiation of murine 3T3-L1 preadipocytes. Dose-responsive inhibition of adipogenesis by several protease inhibitors was noted as measured by reduc ed triglyceride accumulation and attenuated induction of three differentiat ion marker genes - aP2, lipoprotein lipase, and Adipo Q. Potential mechanis ms for altered adipocyte function, including direct binding to PPAR gamma o r inhibition of PPAR gamma-mediated gene transcription were effectively exc luded.