7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13–16 November 2005, Dublin, Ireland

Role of disturbances of brown with respect to white adipocyte biology in HAART-associated lipodystrophy and lipomatosis: studies in vitro and in vivo

ML Rodriguez de la Concepcion¹, JP Guallar¹, P Yubero¹, JC Domingo¹, M Alegre², R Iglesias¹, P Domingo², M Giralt¹ and F Villarroya^1
1Department of Biochemistry and Molecular Biology, University of Barcelona; ²Hospital de la Santa Creu i Sant Pau, Barcelona, Spain

Antiviral Therapy 2005; Supplement 3:L19 (abstract no. 25)

OBJECTIVES: To evaluate the alterations in brown with respect to white adipocyte phenotype in subcutaneous adipose tissue (ScAT) and in lipomas from patients on HAART showing lipodystrophy in comparison to controls, and to determine how drugs of current use in HAART influence brown adipocyte differentiation and gene expression.

METHODS: For studies in vivo, biopsies were obtained from lipomas (dorso-cervical) and from ScAT (abdomen) of patients under HAART showing lipodystrophy, as well as from healthy controls. For studies in vitro, brown preadipocytes in culture were exposed to NRTIs (d4T, ddI, AZT), NNRTIs (nevirapine, efaviernz), NtRTI (tenofovir) or PIs (nelfinavir, saquinavir) and acquisition of brown adipocyte cell morphology was determined. The expression of UCP1 (brown adipocyte-specific marker gene) and of twelve other genes associated to brown and white adipocyte differentiation was analysed (mRNA levels) in cell cultures and in biopsies.

RESULTS: UCP1 mRNA expression was detected only in lipomas and not in ScAT from patients under HAART or in controls. In contrast, PGC-1a, another gene of preferential expression in brown fat, was induced in ScAT respect to controls, but not in lipomas. Other events occurring in ScAT from patients under HAART showing lipodystrophy (downregulation of PPARγ, C/EBPα or Rb mRNA respect to controls) did not occur in lipomas. In cell culture, neither NRTIs nor tenofovir altered the acquisition of brown adipocyte morphology, whereas efavirenz blocked and nevirapine favoured it. Overall gene expression of brown fat markers was activated by nevirapine. UCP1 mRNA was specifically induced by d4T. The other NRTIs and tenofovir had minor effects, whereas efavirenz blocked brown adipocyte gene expression. Among PIs, nelfinavir suppressed brown adipocyte differentiation and gene expression whereas saquinavir had minor effects on differentiation but repressed UCP1.

CONCLUSIONS: Lipomas and ScAT of patients under HAART show a distorted pattern of adipocyte gene expression. In lipomas, several features of brown adipocytes appear but not the acquisition of a full-blown brown fat phenotype. Only minor signs of this phenomenon occur in ScAT. Studies in vitro indicate that antiretroviral drugs had differential effects on brown adipocyte differentiation and gene expression, from activation (nevirapine, d4T) to repression (efavirenz, nelfinavir, saquinavir).

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2005-11-13
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