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OBJECTIVE: We aim to evaluate the mechanisms of rosiglitazone-induced fat recovery in HIV+ patients with lipoatrophy on thymidine Nucleoside Reverse Transcriptase Inhibitors (NRTI) sparing regimens. METHOD: Measures of limb fat (DXA), oxidative stress (F2 isoprostanes) and inflammation [High-sensitivity C-reactive protein (hsCRP), soluble Tumor Necrosis Factor Receptors (sTNFR)-I, sTNFR-II, and interleukin (IL)-6] were performed. Gluteal fat mitochondrial DNA (mtDNA) and peroxisome proliferator-activated receptor (PPAR)-γ RNA [expressed as PPAR-γ/Glyceraldehyde 6-Phosphate Dehydrogenase (GAPDH) RNA ratio] were measured by quantitative PCR. RESULT: 71 patients on thymidine NRTI-sparing regimens were randomized to rosiglitazone vs. placebo for 48 weeks. Duration off thymidine NRTIs was similar between groups. From week 0-48, limb fat increased significantly (p=0.02) more in the rosiglitazone than in the placebo group. Within both groups, F2-isoprostanes, sTNFR-I and sTNFR-II increased significantly (p ≤ 0.003), hsCRP decreased significantly (≤ 0.02), and IL-6 did not change. No differences were seen between groups in any of the inflammation markers. Fat mtDNA (copies/cell) increased nonsignificantly: +41(p=0.08) and +29(p=0.38) within rosiglitazone and placebo group; respectively. PPAR-γ/GAPDH ratio did not change within or between groups. CONCLUSION: Limb fat improvements seen after rosiglitazone were not associated with changes in mtDNA, oxidative or inflammation markers, or PPAR-γ expression. F2 isoprostanes and some of the inflammation markers worsened over time in these subjects on stable ART, regardless of the rosiglitazone assignment. Thus, lipoatrophy can be in part overcome by a separate pathway independent of mitochondrial DNA depletion, such as PPAR-γ.