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.