Reverse transcriptase inhibitors alter uncoupling protein-1 and mitochondrial biogenesis in brown adipocytes.
OBJECTIVE
Human adipose depots contain remnant brown adipocytes interspersed among white adipocytes, and disturbances of brown with respect to white adipocyte biology have been implicated in highly active antiretroviral therapy (HAART)-induced lipomatosis. Brown adipocytes express the uncoupling protein-1 (UCP1) and contain a large number of mitochondria, potential targets of HAART toxicity. The aim of this study was to evaluate the effects of reverse transcriptase inhibitors (RTIs) on primary brown adipocytes differentiated in culture.


METHODS
We analysed the effects of RTIs, nucleoside analogues (NRTIs: stavudine, zidovudine, didanosine and lamivudine) and non-nucleoside analogues (NNRTIs: nevirapine and efavirenz), on differentiation, mitochondrial biogenesis and gene expression in brown adipocytes.


RESULTS
None of the NRTIs altered brown adipocyte differentiation whereas NNTRIs had differing effects. Efavirenz blocked lipid deposition and expression of adipose marker genes but nevirapine induced lipid accumulation and adipose gene expression, promoted mitochondrial biogenesis and increased UCP1. Stavudine, zidovudine and didanosine reduced mitochondrial DNA (mtDNA) content. However, mitochondrial genome expression was only impaired in didanosine-treated adipocytes. Stavudine, but not zidovudine, induced expression of the mitochondrial transcription factors and this may explain compensatory mechanisms for the depletion of mtDNA by up-regulating mtDNA transcription. Stavudine caused a specific induction of UCP1 gene expression through direct interaction with a retinoic acid-dependent pathway.


CONCLUSIONS
Specific disturbances in brown adipocytes in adipose depots may contribute to HAART-induced lipomatosis. Mitochondrial depletion does not appear to be the only mechanism explaining adverse effects in brown adipocytes because there is evidence of compensatory mechanisms that maintain mtDNA expression, and the expression of the UCP1 gene is specifically altered.
Rodríguez de la Concepción
M Luisa
ML
Department de Bioquímica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
Yubero
Pilar
P
Domingo
Joan C
JC
Iglesias
Roser
R
Domingo
Pere
P
Villarroya
Frcancesc
F
Giralt
Marta
M
D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007473:Ion Channels; D008565:Membrane Proteins / Q000096:biosynthesis*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D004272:DNA, Mitochondrial; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018894:Reverse Transcriptase Inhibitors; D014157:Transcription Factors; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1