The HIV-1 nucleoside reverse transcriptase inhibitors stavudine and zidovudine alter adipocyte functions in vitro.
OBJECTIVE
Nucleoside analogues are suspected of playing a role in peripheral fat loss in patients during long-term treatment with antiretroviral drugs.


METHODS
We compared the long-term effects of stavudine (10 microM), zidovudine (1 muM), didanosine (10 microM), abacavir (4 microM), lamivudine (10 microM), and tenofovir (1 microM), near their maximum concentration values, on the differentiation, lipid accumulation, survival and mitochondrial function of differentiating 3T3-F442A and differentiated 3T3-L1 adipocytes.


RESULTS
None of the nucleoside reverse transcriptase inhibitors (NRTI) markedly altered the differentiation of 3T3-F442A cells, as shown by the unmodified percentage of cells with lipid droplets on day 7 and the expression of the early differentiation markers CCAAT/enhancer binding protein (C/EBP) beta (on day 2) and sterol regulatory element-binding protein. However, stavudine and zidovudine altered the lipid phenotype, decreasing the lipid content and expression of markers involved in lipid metabolism, namely C/EBPalpha, peroxisome proliferator-activated receptor gamma, adipocyte lipid binding protein 2, fatty acid synthase and acetyl-coenzyme A carboxylase. Stavudine and zidovudine, contrary to the other NRTI, drove 5-10% of 3T3-F442A cells towards apoptosis, and reduced the lipid content and survival of differentiated 3T3-L1 adipocytes. Stavudine and zidovudine increased mitochondrial mass by two to fourfold, and lowered the mitochondrial membrane potential (JC-1 stain) as did zalcitabine (0.2 microM). Co-treatment with zidovudine plus lamivudine, or zidovudine plus lamivudine and abacavir, did not increase the effect of zidovudine on cell viability or apoptosis.


CONCLUSIONS
The thymidine analogues stavudine and zidovudine decreased lipid content, mitochondrial activity, and adipocyte survival in vitro.
Caron
Martine
M
INSERM U402, Faculté de Médecine Saint-Antoine, Université Pierre et Marie Curie, Paris, France. caron@st-antoine.inserm.fr
Auclair
Martine
M
Lagathu
Claire
C
Lombès
Anne
A
Walker
Ulrich A
UA
Kornprobst
Michel
M
Capeau
Jacqueline
J
D041721:3T3-L1 Cells; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D016049:Didanosine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology*; D039682:HIV-Associated Lipodystrophy Syndrome / Q000139:chemically induced / Q000378:metabolism / Q000821:virology; D019259:Lamivudine / Q000494:pharmacology; D050356:Lipid Metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology*; D000068698:Tenofovir; D015215:Zidovudine / Q000494:pharmacology*; D000099227:Abacavir
D000225:Adenine; D016049:Didanosine; D015224:Dideoxynucleosides; D019259:Lamivudine; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D000068698:Tenofovir; D015215:Zidovudine; D000099227:Abacavir