Carr, A.

Cooper, D.

Emery, S.

Kelleher, A.

Mallal, S.

Mallon, P.

Nolan, D.

Rogers, G.

Samaras, K.

Sedwell, R.

Unemori, P.

Wand, H.

English

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41 The Effect of Rosiglitazone on PPARγ Expression in Human Adipose Tissue Is Limited by Continued Exposure to Thymidine NRTI Patrick Mallon*1,2, R Sedwell1, G Rogers3, D Nolan4, P Unemori1, H Wand1, K Samaras5, A Kelleher1,2, S Emery1, D Cooper1,2, 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 β-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.                                                     PPARγ    Week 2  Week 48    tNRTI  no tNRTI  tNRTI  no tNRTI RSG  12 [99]  68 [56]  –22 [154]  87 [166] Placebo  2 [97]  7 [173]  –32 [131]  74 [181]                                                   PGC-1 RSG  13 [69]  149 [341]  29 [63]  672 [976] Placebo  35 [131]  107 [181]  119 [118]  313 [220] Keywords: Lipodystrophy; Rosiglitazone; Mitochondrial toxicity  

The effect of rosiglitazone on PPARg expression in human adipose tissue Is limited by continued exposure to thymidine NRTI

Unemore, P.

The effect of rosiglitazone on PPAR gamma expression in human adipose tissue is limited by continued exposure to thymidine NRTI

http://researchrepository.murdoch.edu.au/15675/

The effect of rosiglitazone on PPARg expression in human adipose tissue Is limited by continued exposure to thymidine NRTI

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