Differential adipose tissue remodeling and metabolic effects of dolutegravir and bictegravir: implications for HIV therapy

Combined antiretroviral therapy (cART) has significantly improved the prognosis of people with HIV (PWH), but long-term metabolic side effects-particularly weight gain and adipose tissue dysfunction-remain an important concern. Among the components of cART, integrase strand transfer inhibitors (INSTI), especially dolutegravir (DTG) and bictegravir (BIC), have been related to adipose tissue remodeling and weight change. This study explores the direct effects of DTG and BIC on adipogenesis and adipose tissue function using 3T3-L1 preadipocyte cultures and mouse models. In vitro, DTG impaired adipocyte differentiation, suppressed adipogenic and metabolic gene expression, reduced lipid accumulation, and elevated profibrotic markers. In contrast, BIC accelerated adipogenesis and promoted the development of hypertrophic adipocytes. Both INSTI downregulated adipokine production, with DTG having a more pronounced effect. In vivo, neither drug significantly altered total body fat or food intake in mice, but both were associated with increased weight gain trends and a stronger correlation between body weight and fat depot mass. RNA sequencing of perigonadal white adipose tissue (WAT) revealed distinct sets of differentially expressed genes (DEGs) in DTG- and BIC-treated mice, with overlapping alterations in genes involved in adipocyte differentiation, lipid metabolism, and circadian regulation. Collectively, these findings demonstrate that DTG and BIC exert distinct yet overlapping influences on adipogenesis and WAT biology that might contribute to metabolic alterations in PWH. Understanding these mechanisms is essential for optimizing long-term HIV treatment strategies and mitigating the cardiometabolic risk associated with modern antiretroviral regimens.