Inhibition of Adipose Tissue Beiging by HIV Integrase Inhibitors, Dolutegravir and Bictegravir, Is Associated with Adipocyte Hypertrophy, Hypoxia, Elevated Fibrosis, and Insulin Resistance in Simian Adipose Tissue and Human Adipocytes

Cells. 2022 Jun 4;11(11):1841. doi: 10.3390/cells11111841.


For people living with HIV, treatment with integrase-strand-transfer-inhibitors (INSTIs) can promote adipose tissue (AT) gain. We previously demonstrated that INSTIs can induce hypertrophy and fibrosis in AT of macaques and humans. By promoting energy expenditure, the emergence of beige adipocytes in white AT (beiging) could play an important role by limiting excess lipid storage and associated adipocyte dysfunction. We hypothesized that INSTIs could alter AT via beiging inhibition. Fibrosis and gene expression were measured in subcutaneous (SCAT) and visceral AT (VAT) from SIV-infected, dolutegravir-treated (SIVART) macaques. Beiging capacity was assessed in human adipose stromal cells (ASCs) undergoing differentiation and being exposed to dolutegravir, bictegravir, or raltegravir. Expression of beige markers, such as positive-regulatory-domain-containing-16 (PRDM16), were lower in AT of SIVART as compared to control macaques, whereas fibrosis-related genes were higher. Dolutegravir and bictegravir inhibited beige differentiation in ASCs, as shown by lower expression of beige markers and lower cell respiration. INSTIs also induced a hypertrophic insulin-resistant state associated with a pro-fibrotic phenotype. Our results indicate that adipocyte hypertrophy induced by INSTIs is involved via hypoxia (revealed by a greater hypoxia-inducible-factor-1-alpha gene expression) in fat fibrosis, beiging inhibition, and thus (via positive feedback), probably, further hypertrophy and associated insulin resistance.

Keywords: HIV integrase inhibitors; adipose tissue; beiging; fibrosis; hypertrophy; insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / metabolism
  • Adipose Tissue
  • Amides
  • Fibrosis
  • HIV Integrase Inhibitors* / pharmacology
  • HIV Integrase Inhibitors* / therapeutic use
  • Heterocyclic Compounds, 3-Ring
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Hypertrophy / metabolism
  • Hypoxia / metabolism
  • Insulin Resistance*
  • Oxazines
  • Piperazines
  • Pyridones


  • Amides
  • HIV Integrase Inhibitors
  • Heterocyclic Compounds, 3-Ring
  • Heterocyclic Compounds, 4 or More Rings
  • Oxazines
  • Piperazines
  • Pyridones
  • bictegravir
  • dolutegravir

Grants and funding

Part of this research was funded by Sidaction [PhD grant number 13006 for K.NA.], “Programme Investissements d’Avenir” R.G.L.: ANR-11-INBS-0008 infrastructure and ANR-10-EQPX-02-01, J.C.: RHU-ANR-15-RHUS-0003.