Antiretroviral‐Related Adipocyte Dysfunction and Lipodystrophy in HIV‐Infected Patients: Alteration of the PPARγ‐Dependent Pathways

Lipodystrophy and metabolic alterations are major complications of antiretroviral therapy in HIV-infected patients. In vitro studies using cultured murine and human adipocytes revealed that some protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were implicated to a different extent in adipose cell dysfunction and that a chronic incubation with some PIs decreased mRNA and protein expression of PPAR γ . Defective lamin A maturation linked to PI inhibitory activity could impede the nuclear translocation of SREBP1c, therefore, reducing PPAR γ expression. Adipose cell function was partially restored by the PPAR γ agonists, thiazolidinediones. Adverse effects of PIs and NRTIs have also been reported in macrophages, a cell type that coexists with, and modulates, adipocyte function in fat tissue. In HIV-infected patients under ART, a decreased expression of PPAR γ and of PPAR γ -related genes was observed in adipose tissue, these anomalies being more severe in patients with ART-induced lipoatrophy. Altered PPAR γ expression was reversed in patients stopping PIs. Treatment of patients with agonists of PPAR γ could improve, at least partially, the subcutaneous lipoatrophy. These data indicate that decreased PPAR γ expression and PPAR γ -related function, resulting from ART-induced adipose tissue toxicity, play a central role in HIV-related lipoatrophy and metabolic consequences.