Tenofovir alafenamide promotes weight gain and impairs fatty acid metabolism-related signaling pathways in visceral fat tissue compared to tenofovir disoproxil fumarate

Abstract

Modern antiretroviral therapy (ART) is associated with rapid weight gain, which appears to be antiretroviral-specific. Tenofovir is a nucleoside reverse transcriptase inhibitor commonly employed as a backbone in many ART formulations. Tenofovir alafenamide (TAF) has been associated with significant weight gain in people living with HIV (PLWH) initiating ART. Interestingly, tenofovir disoproxil fumarate (TDF), has no impact on weight or may even be weight suppressive. The current study compared the impact of two tenofovir-based ART formulations on weight and adipose tissue. We utilized a humanized mouse model of HIV-infection and administered two clinically relevant ART combinations TAF/dolutegravir (DTG)/emtricitabine (FTC) and TDF/DTG/FTC. As expected, female mice treated with TAF/DTG/FTC had the greatest weight gain and fat accumulation, as measured by dual energy x-ray absorptiometry (DXA). As ART-induced accumulation of visceral adipose tissue is linked to mortality, we isolated visceral adipose tissue for targeted (qPCR) and non-targeted (RNAseq) gene expression. Mice treated with TAF/DTG/FTC had increased expression of adipocyte differentiation related genes, leptin and PPAR-γ. RNAseq revealed that while the expression patterns for both TAF/DTG/FTC and TDF/DTG/FTC treated mice were similar, there were key differences. Specifically, KEGG pathway analysis indicated that TAF/DTG/FTC treated mice showed suppression of multiple fatty acid metabolism related pathways, while TDF/DTG/FTC treated mice showed evidence for increased thermogenesis. The results suggest that weight gain associated with TAF-based ART may be due to impaired adipocyte mediated lipid handling, while suppressed weight gain with TDF-based ART may be secondary to increased browning of visceral adipocytes, although independent validation is necessary.