12th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 22-25, 2005

Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 41

Patrick Mallon^1,2, R Sedwell¹, G Rogers³, D Nolan⁴, P Unemori¹, H Wand¹, K Samaras⁵, A Kelleher^1,2, S Emery¹, D Cooper^1,2, A Carr², and The Rosey Investigators
¹Natl Ctr in HIV Epidemiology and Clin Res, Univ of New South Wales, Sydney, Australia; ²St Vincent's Hosp, Sydney, Australia; ³Univ of Adelaide, Australia; ⁴Royal Perth Hosp, Australia; and ⁵Garvan Inst of Med Res, Sydney, Australia

BACKGROUND: Decreases in peroxisome proliferators-activated receptor gamma ( PPAR-γ) expression in subcutaneous adipose tissue may be important in the pathogenesis of lipoatrophy. Despite this, rosiglitazone (RSG), a PPAR-γ agonist, has not been shown to increase limb fat in lipoatrophic HIV-infected patients.

METHODS: We completed a sub-study of a randomized, placebo-controlled, 48-week trial examining the effect of RSG 4 mg twice daily on limb fat in 100 HIV-infected adults with lipoatrophy. We examined changes in mRNA expression in subcutaneous fat biopsies, performed at weeks 0, 2, and 48. RNA was extracted and real-time RT-PCR performed for mitochondrial and lipid metabolism genes, with results presented relative to b-actin expression, which did not change. Non-parametric analyses were applied.

RESULTS: We recruited 44 men (RSG n = 21, placebo n = 23) to this sub-study of which 21 were receiving the thymidine analogues (tNRTI) zidovudine (AZT) (n = 3) or stavudine (d4T) (n = 18) at baseline. Although groups were matched for baseline PPAR-γ expression (p = 0.8), limb fat was lower in the RSG group (1.9 kg vs 2.3kg). Mitochondrial-encoded cytochrome-b expression was significantly lower in those treated with tNRTI (median 2.53 [IQR 4.45] vs 6.04 [4.54] for the no-tNRTI group, p = 0.001). At week 2, only those randomized to RSG in the no-tNRTI group experienced a significant rise in PPAR-γ expression (p = 0.046). Similar significant increases in PPAR-γ co-activator 1 (PGC-1) expression were also observed in the RSG no-tNRTI group. At week 48, PPAR-γ expression was significantly higher only in the no-tNRTI group, regardless of randomized treatment allocation (p = 0.04), with RSG having no effect in the tNRTI group (see the table). No significant correlations were observed between changes in PPAR-γ or PGC-1 expression and change in limb fat.

CONCLUSIONS: In subcutaneous adipose tissue of lipoatrophic, HIV-infected males, the effect of RSG on PPAR-γ expression appears limited by continued exposure to thymidine NRTI. These results provide further insight into the effect of mitochondrial toxicity on PPAR-γ expression and provide a potential molecular explanation for the lack of clinical effect of RSG on limb fat in this patient group.

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Copyright © 2005 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.