Lipodystrophy associated with highly active anti-retroviral therapy for HIV infection: the adipocyte as a target of anti-retroviral-induced mitochondrial toxicity.

The lipodystrophy syndrome and associated metabolic alterations are the most prevalent adverse effects in HIV-infected patients taking highly active anti-retroviral therapy (HAART). This syndrome involves profound disturbances in adipose tissue. The toxic effect of nucleoside reverse transcriptase inhibitors on mitochondrial function is a major contributor to the lipodystrophy syndrome. Although adipocytes were not expected to be preferential targets of mitochondrial toxicity, recent re-evaluation of the role of mitochondria in white adipocytes helps to explain the molecular basis of HAART-associated lipodystrophy. Adipocytes are a source of paracrine and endocrine signals that influence adipocyte biology and systemic metabolism. Mitochondrial disturbances elicited by HAART result in an abnormal perception of the bioenergetic status by adipocytes, thus leading to enhancement of catalytic pathways and apoptosis in peripheral adipose tissue, alterations in the differentiation of brown versus white adipocytes, and the release of hormonal signals that lead to systemic metabolic disturbances.