7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13–16 November 2005, Dublin, Ireland

ZIDOVUDINE INHIBITS ADIPOGENIC DIFFERENTIATION OF 3T3-L1 CELLS THROUGH INHIBITION OF CLONAL EXPANSION

M Stankov¹, RE Schmidt¹ and GMN Behrens^1
1 Hannover Medical School, Hannover, Germany

Antiviral Therapy 2005; Supplement 3:L20 (abstract no. 26)

OBJECTIVES: To investigate the effects of zidovudine on adipogenesis, adipocyte survival and the development of lipoatrophy in 3T3-L1 preadipocytes and primary human fibroblasts.

METHODS: We studied proliferation, adipocyte phenotype, viability, differentiation, [CCAAT/enhancer-binding protein (C/EBP)-β, CCAAT/enhancer-binding protein (C/EBP)-α, peroxisome proliferators-activated receptor (PPAR)-γ expression] and adiponectin production in 3T3- L1 adipocytes. Cells were exposed to zidovudine (6 µM or 180 µM), at different developmental stages for up to 21 days. Gene expression was assessed using real-time PCR. Fat content was measured with oil red O staining and adiponectin production by real-time PCR and ELISA. Proliferation was assessed with thymidine incorporation, total cellular protein, and cell numbers.

RESULTS: We observed an inhibitory effect of zidovudine to critical early events in preadipocyte differentiation, namely the completion of the mitotic clonal expansion. When induced to differentiate in the presence of zidovudine, 3T3-L1 preadipocytes failed to accumulate cytoplasmic triacylglycerol as well as failing to express normal levels of the adipogenic transcription factors C/EBP-α, C/EBP)-β and PPAR-γ. Incomplete differentiation resulted in the reduction of adiponectin production and expression.

CONCLUSIONS: Zidovudine impairs the proliferative activity in preadipocytes. Inhibition of clonal expansion during conversion from the 3T3-L1 preadipocyte into fully differentiated adipocytes appears to be the critical step of the zidovudine anti-adipogenic effect.

ACKNOWLEDGEMENTS:: Supported by competence network HIV/AIDS C15.

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2005-11-13
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