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Differential Effects of Raltegravir, Dolutegravir and Bictegravir on Human Adipocytes

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Differential Effects of Raltegravir, Dolutegravir and Bictegravir on Human Adipocytes Differential effects of raltegravir, dolutegravir and bictegravir on human adipocytes Pere Domingo1, Tania Quesada-López2, Joan Villarroya1,2, Mar Gutierrez1, Gracia Mateo1, Isabel Mur1, Noemí Corbacho1, Joan Carles Domingo2, Francesc Villarroya2, Marta Giralt2 1 Department of Infectious Diseases, Hospital de la Santa Creu i Sant Pau, and Institut de Recerca del Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia; 2 Departament de Bioquímica i Biomedicina Molecular and Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Catalonia, and CIBER Fisiopatología de la Obesidad y Nutrición, Spain Background Methods Recent data have raised concerns about weight gain Human Simpson Golabi Behmel Syndrome (SGBS) adipose cells were used and cultured associated with the use of integrase strand transfer using standard procedures. In controls, sub-optimal differentiation was achieved with the use inhibitors (INsTI) [1-3]. The pathophysiological basis of 0.5 μM rosiglitazone at the time of differentiation induction. Drugs were included in the of this effect is unknown. differentiation medium at concentrations ranging from 0.1 to 10 μM (which includes Cmin and The goal of our study was to assess the potential Cmax in treated patients. direct effects of raltegravir (RAL), dolutegravir (DTG), Morphological adipogenesis (accumulation of lipid droplets) was followed. and bictegravir (BIC) on human adipose cells. Gene expression for markers of adipogenesis, adipocyte metabolism, adipokines, and cytokines was determined using qRT-PCR twelve days after induction of differentiation. Results Figure 1. Effects of INsTI on human adipose cell differentiation • Morphological differentiation of human adipose cells in culture was None of the three INsTI tested caused substantial effects on unaffected by the presence of BIC, DTG or RAL (Fig.1). Control • Expression of marker genes of adipogenesis, such as glucose overall adipogenesis, either transporter GLUT4 (Fig.2a), lipoprotein lipase (Fig.2b), and also the positive or negative. adipokine leptin (Fig.2c), were unaltered. • Expression of inflammation-related cytokines (IL-6, MCP-1) was not 0.1 μM 1 μM 10 μM induced by INsTIs (Fig.2e and 2f), and even significantly decreased at 10 μM by BIC and DTG (only MCP-1). • Both RAL and DTG lowered adiponectin gene expression in a dose- Bictegravir dependent manner (Fig.2d). • Maximal inhibition noted at 10 μM (~ 60% and 40% inhibition for RAL and DTG, respectively), relative to expression in controls. In contrast, BIC did not show such an effect (Fig.2d). 0.1 μM 1 μM 10 μM Conclusions Dolutegravir • INsTI did not cause large effects on human adipose cell differentiation (Fig.1; Fig.2a;2b;2c). • BIC and DTG, but not RAL, reduced gene expression of pro- 0.1 μM 1 μM 10 μM inflammatory cytokines (Fig.2e and 2f). • RAL and DTG, but not BIC, reduced adiponectin gene expression (Fig.2d). Raltegravir • Further studies are necessary to ascertain the pathophysiological relevance of these findings with respect to the effects of INSTI- containing treatments on body weight and metabolism in people living Representative photomicrographs from three experiments of adipocyte cell with HIV. cultures differentiating in the presence of the indicated concentrations of drugs. a.Figure Markers 2. Effects of adipogenesis of INsTI on gene expression b. Adipokines in human adipocytes differentiating c. Inflammation in culture Control References Bictegravir 1. Eckard AR, McComsey GA. Weight gain and a S L C 2 A 4 m R N A c L E P m R N A e Dolutegravir integrase inhibitors. Curr Opin Infect Dis. Glucose transporter GLUT4 Leptin mRNA IL-6I LmRNA6 m R N A Raltegravir 2020 Feb;33(1):10-19. 2 .5 SLC2A4 mRNA 1 .5 3 2. Koethe JR, Lagathu C, Lake JE, Domingo P, Calmy A, Falutz J, Brown TT, Capeau J. HIV 2 .0 n n n and antiretroviral therapy-related fat o o i i 1 .0 o t t i 2 t c c 1 .5 alterations.Nat Rev Dis Primers. 2020 6(1):48. c u u u d d 3. Gorwood J, et al. The integrase inhibitors d n n i i n dolutegravir and raltegravir exert pro- 1 .0 i d d l l 0 .5 d l o adipogenic and profibrotic effects and induce o 1 o F F 0 .5 F * * insulin resistance in human/simian adipose tissue and human adipocytes. Clin Infect Dis. 0 .0 0 .0 2020 Mar 13:ciaa259. Epub ahead of print. 0 l ( M ) l 1 1 1 ( M ) o ,1 1 0 ,1 1 0 ,1 1 0 o , 1 0 , 1 0 , 1 0 r 0 1 0 1 0 1 r 0 1 0 1 0 1 l 1 1 0 1 1 0 1 1 0 ( M ) t t o , 1 , 1 , 1 n n tr 0 0 0 o o n Acknowledgements C B ic te g ra v ir D o lu te g r a v ir R a lte g ra v ir C B ic te g ra v ir D o lu te g r a v ir R a lte g ra v ir o C B ic te g ra v ir D o lu te g r a v ir R a lte g ra v ir This work has been partially funded b LipoproteinL P L m lipaseR N A d A D IP O Q m R N A f C C L 2 m R N A Adiponectin mRNA MCP-1/ CCL-2 mRNA by Instituto de Salud Carlos III (FIS 2 .0 LPL mRNA 1 .5 2 .0 PI17/0420 and PI17/0498), n 1 .5 n n 1 .5 cofinanced by the European o o i o i i t 1 .0 t t c c c Regional Development Fund u u u d * 1 .0 d d 1 .0 n n i n (ERDF), and an independent grant i * i d d l d l 0 .5 l * o o * from Gilead. This company had no * o F 0 .5 F * * * F 0 .5 role in the study design, data collection, and interpretation of data. 0 .0 0 .0 0 .0 l 1 1 0 1 1 0 1 1 0 ( M ) l ( M ) o , , , o ,1 1 0 ,1 1 0 ,1 1 0 l 1 0 1 0 1 0 ( M ) r 0 1 0 1 0 1 r 1 1 1 o , 1 , 1 , 1 t t 0 0 0 r 0 1 0 1 0 1 n n t o o n Contact Information o C C B ic te g ra v ir D o lu te g r a v ir R a lte g ra v ir B ic te g ra v ir D o lu te g r a v ir R a lte g ra v ir C B ic te g ra v ir D o lu te g r a v ir R a lte g ra v ir Pere Domingo Data (means ± SEM) from three experiments, and expressed relative to values from untreated control cells. *P < 0.05 vs. control. [email protected] Poster 4923533.
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