Background: Antiretroviral therapy has been associated with lipodystrophy, characterised by visceral fat accumulation and subcutaneous atrophy. The mechanisms of this are not well understood, although regio-specific differences in the expression of various genes involved in adipogenesis may be important. We have investigated the effects of both PI and NRTI on adiponectin and TNF-a expression in isolated human mature adipocytes taken from both subcutaneous and visceral compartments.

Methods:  Mature adipocytes were isolated from paired omental and subcutaneous adipose tissue samples obtained from 8 HIV- patients (body mass index 22.98±1.9) undergoing routine abdominal surgery. Ethical approval was obtained.  Following collagenase digestion, the diluted fat cell suspensions (5 to 10,000 cells/mL) were incubated in duplicate for 2 hours at 37°C in the presence (10 µM) or absence of zidovudine, stavudine, indinavir, ritonavir, saquinavir, nelfinavir, and atazanavir. Quantification of mRNA expression was assessed using real time PCR. Differences in expression were assessed using the CT method and normalized to b-actin.

Results:   Adiponectin, but not TNF-a mRNA expression, was higher in drug-naïve subcutaneous than in omental adipocytes (p <0.001).  Both NRTI and PI, apart from atazanavir, significantly (p <0.01) reduced adiponectin expression in sc adipocytes.  With om adipocytes, there was a smaller effect, which did not attain statistical significance, with the exception of RTV, SQV, and NFV (p <0.05) treated cells.  ATV significantly (p <0.001) increased adiponectin expression in omental adipocytes. By contrast, TNF-a was up regulated in RTV, SQV, and NFV treated subcutaneous (3.7; 3.6- and 6.8-fold change vs control, p <0.05) and omental treated cells (5.1-,  5.2-, and 7.9-fold change, respectively, o <0.05), while ZDV, D4T, IDV, and ATV had no effect on both depots. Adiponectin mRNA expression was inversely correlated to TNF-a mRNA levels in both subcutaneous (r = -0.5, p <0.01) and om (r = -0.3, p <0.05) adipocytes.

Conclusions:   Our data show that both PI (except ATV) and NRTI down-regulate adiponectin, an adipokine known to improve insulin sensitivity, in a regio-specific manner. TNF-a expression is also perturbed by some, but not all of the antiretrovirals tested.  Interestingly, however, our data supports recent findings of an inverse relationship between TNF-a and adiponectin, perturbations of which may be involved in the pathogenesis of lipodystrophy.

Keywords: Adipokines; Lipodystrophy; Regional Differences