HIV protease inhibitor-specific alterations in human adipocyte differentiation and metabolism.
OBJECTIVE
Human immunodeficiency virus (HIV) patients on antiretroviral regimens frequently develop a syndrome of abnormal fat distribution, insulin resistance, and dyslipidemia. This lipodystrophic syndrome has been most closely linked to the use of HIV protease inhibitors (PIs). Several mechanisms have been postulated to explain these adverse effects of PIs, based largely on studies of rodent adipocytes. Intriguingly, atazanavir, a newer PI equally effective against HIV, is associated with fewer signs of lipodystrophy. We hypothesized that the less deleterious clinical effects of atazanavir would be reflected in physiological differences observed in PI-treated adipocytes.


METHODS
We compared the effects of atazanavir and an older PI associated with lipodystrophy, ritonavir, on differentiation, gene expression, adipocytokine secretion, and insulin signaling in a human adipocyte cell line.


RESULTS
Ritonavir inhibited human adipocyte differentiation and induced apoptosis to a greater extent than atazanavir. Treatment of mature adipocytes with ritonavir, but not atazanavir, also selectively decreased insulin signaling. Moreover, ritonavir also selectively decreased expression of adiponectin, an insulin-sensitizing adipocytokine, while inducing interleukin-6, a proinflammatory cytokine implicated in insulin resistance.


CONCLUSIONS
These data suggest that the distinct metabolic side effect profiles of these PIs could be a consequence of their differential effects on adipocyte physiology.
Kim
Roy J
RJ
Division of Endocrinology, Children's Hospital of Philadelphia, Pennsylvania, USA.
Wilson
Camella G
CG
Wabitsch
Martin
M
Lazar
Mitchell A
MA
Steppan
Claire M
CM
D017667:Adipocytes / Q000187:drug effects*; D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D052242:Adiponectin / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000009:adverse effects*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*
D052242:Adiponectin; D017320:HIV Protease Inhibitors; C508600:IL6 protein, human; D007328:Insulin; D015850:Interleukin-6