2. Academic Validation
  3. Differential adipose tissue remodeling and metabolic effects of dolutegravir and bictegravir: implications for HIV therapy

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

  • Biomed Pharmacother. 2025 Dec:193:118831. doi: 10.1016/j.biopha.2025.118831.
Laura Gisbert-Ferrándiz 1,  Patricia García-Martínez 2,  Juan V Esplugues 3,  Ángeles Álvarez-Ribelles 4,  Ana Blas-García 5
Affiliations

Affiliations

  • 1 Departamento de Farmacología, Universitat de València, Valencia, Spain; Fundación para el Fomento de la Investigación Sanitaria y Biomédica en la Comunidad Valenciana (FISABIO), Hospital Universitario Doctor Peset, Valencia, Spain. Electronic address: [email protected].
  • 2 Departamento de Farmacología, Universitat de València, Valencia, Spain; Fundación para el Fomento de la Investigación Sanitaria y Biomédica en la Comunidad Valenciana (FISABIO), Hospital Universitario Doctor Peset, Valencia, Spain. Electronic address: [email protected].
  • 3 Departamento de Farmacología, Universitat de València, Valencia, Spain; Fundación para el Fomento de la Investigación Sanitaria y Biomédica en la Comunidad Valenciana (FISABIO), Hospital Universitario Doctor Peset, Valencia, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. Electronic address: [email protected].
  • 4 Departamento de Farmacología, Universitat de València, Valencia, Spain; Fundación para el Fomento de la Investigación Sanitaria y Biomédica en la Comunidad Valenciana (FISABIO), Hospital Universitario Doctor Peset, Valencia, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Spain. Electronic address: [email protected].
  • 5 Fundación para el Fomento de la Investigación Sanitaria y Biomédica en la Comunidad Valenciana (FISABIO), Hospital Universitario Doctor Peset, Valencia, Spain; Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd), Spain; Departamento de Fisiología, Universitat de València, Valencia, Spain. Electronic address: [email protected].
PMID: 41317481 DOI: 10.1016/j.biopha.2025.118831
Abstract

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.

Keywords

adipocytes; adipogenesis; antiretroviral therapy; body composition; integrase inhibitors; weight gain.

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