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Antiretroviral drugs alter adipocyte metabolism: a possible role for polyunsaturated fatty acids in mitigating HIV lipodystrophy

Published online by Cambridge University Press:  19 October 2012

C. Loonam ,
S. O'Dell  and
A. Mullen
C. Loonam
Affiliation:
Diabetes & Nutritional Sciences Division, Franklin-Wilkins Building, King's College London, 150 Stamford Street, London, SE19NH, UK
S. O'Dell
Affiliation:
Diabetes & Nutritional Sciences Division, Franklin-Wilkins Building, King's College London, 150 Stamford Street, London, SE19NH, UK
A. Mullen
Affiliation:
Diabetes & Nutritional Sciences Division, Franklin-Wilkins Building, King's College London, 150 Stamford Street, London, SE19NH, UK
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Abstract

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Abstract
Information
Proceedings of the Nutrition Society , Volume 71 , Issue OCE2: Summer Meeting hosted by the Irish Section, 16–19 July 2012, Translational nutrition: integrating research, practice and policy , 2012 , E120
Copyright
Copyright © The Authors 2012

HIV-associated lipodystrophy syndrome (HALS), a side-effect of anti-retroviral therapy (ART), is characterised by peripheral fat wasting, central obesity, dyslipidaemia, insulin resistance, inflammation and endothelial dysfunction( Reference Bradbury and Samaras 1 ). HALS affects up to 83% of patients receiving ART and is associated with an increased risk of accelerated T2DM and CVD( Reference Samaras, Gan and Peake 2 ). PPAR-γ signalling, normally initiated by fatty acid and prostanoid ligands( Reference Xu, Lambert and Montana 3 ), has been shown to be down-regulated as a result of ART and plays a central role in development of abnormal adipocyte function, gene expression and inflammatory profile, which contribute to the development of HALS( Reference Caron, Vigouroux and Bastard 4 ).

We examined the effects of a number of anti-retroviral drugs (nucleoside reverse transcriptase inhibitors zidovudine and stavudine, nucleotide reverse transcriptase inhibitor tenofovir and protease inhibitors ritonavir and indinavir) at physiological concentrations, on lipid accumulation, adipokine secretion, and gene expression in the 3T3-L1 mouse adipocyte cell line.

We showed (by Oil Red O staining) that pre-adipocytes differentiating in the presence of ritonavir accumulated significantly less triglyceride relative to the vehicle (ethanol) control (29%; P=0.001). Ritonavir caused a significant decrease in PPAR-γ gene expression (51%; P=0.004) and in secretion of its target gene product, the anti-inflammatory cytokine adiponectin (97%; P<0.001). Adiponectin secretion was also reduced by indinavir (21%; P=0.001) and tenofovir (30%; P<0.001) relative to vehicle control. Significant increases in expression of pro-inflammatory resistin (P=0.001), leptin (P<0.001) and IL-6 genes (P<0.001) were caused by tenofovir, in leptin by zidovudine (P=0.005) and in IL-6 by indinavir (P=0.017).

These results indicate the detrimental effect of ART on triglyceride accumulation, adiponectin secretion and expression of genes involved in inflammation. Ongoing work is investigating whether long chain polyunsaturated fatty acids, as activating ligands for PPAR-γ, can mitigate these effects on adipocyte function, gene expression and inflammation by increasing adiponectin secretion and down-regulating resistin, leptin and IL-6.

References

1. Bradbury, RA & Samaras, K (2008) Diabetes Obes Metab 10, 441–450.CrossRefGoogle Scholar
2. Samaras, K, Gan, SK, Peake, PW et al. (2009) Obesity 17, 58–59.CrossRefGoogle Scholar
3. Xu, HE, Lambert, MH, Montana, VG et al. (1999) Mol Cell 3, 397–403.CrossRefGoogle Scholar
4. Caron, M, Vigouroux, C, Bastard, JP et al. (2009) PPAR Res 2009, 507–141.CrossRefGoogle Scholar