Altered Adipokine Response in Murine 3T3-F442A Adipocytes Treated with Protease Inhibitors and Nucleoside Reverse Transcriptase Inhibitors

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Abstract
Background: Abnormal levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and adiponectin have been observed in HIV patients with lipodystrophy. However, because these patients have long drug and disease histories, it is unclear which drugs are responsible for these abnormalities. We have therefore investigated the effects of individual antiretrovirals on adipokine expression and adipogenesis using a murine cell line in vitro. Methods: Differentiating murine 3T3-F442A adipocytes were incubated with 20 μM nucleoside reverse transcriptase inhibitors (NRTIs) zidovudine or stavudine, or protease inhibitors (PIs) indinavir, ritonavir, saquinavir or nelfinavir, in the presence and absence of rosiglitazone (10 μM). Adipogenesis was assessed using glycerol-3-phosphate dehydrogenase activity, while expression of TNF-α, IL-6 and adiponectin at protein and mRNA levels was assessed by ELISA and quantitative real-time PCR, respectively. Results: Nelfinavir, ritonavir and saquinavir inhibited adipogenesis and up-regulated the expression of TNF-α and IL-6, but this effect was not seen with indinavir, zidovudine and stavudine. Adiponectin expression was significantly reduced in both NRTI- and PI-treated cells, although the most profound reductions were found with ritonavir and saquinavir. Co-incubation with rosiglitazone led to a partial attenuation of the change in TNF-α, IL-6 and adiponectin secretion. Conclusions: Our data suggest that the PIs nelfinavir, ritonavir and saquinavir have potent effects in inhibiting adipocyte differentiation whilst up-regulating TNF-α and IL-6 mRNA levels and decreasing adiponectin levels. These changes were partially attenuated by rosiglitazone. Taken together, the data show that antiretrovirals have complex effects on adipocyte function, which may be mediated by an altered adipokine response.

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