Some INSTIs inhibit the beiging capacity of white adipose tissue in vivo and in vitro, resulting in dysfunctional hypertrophic adipose tissue

Some HIV-infected patients receiving an integrase strand transfer inhibitor (INSTI), especially dolutegravir (DTG) and bictegravir (BIC), display an accumulation of adipose tissue (AT) leading to weight gain which is associated with increased cardiometabolic risk. Adipose tissue (AT) plays an essential role in energy homeostasis through its storage and secretory functions. White AT, which plays a critical role in energy storage and mobilization, can be distinguished from brown and beige AT, which exert a thermogenic function linked to the expression of the uncoupling protein UCP1 and to the increased oxidation of fatty acids. The emergence of beige adipocytes in white AT (beiging) can be induced by adrenergic agents or cold and is beneficial to whole AT homeostasis by promoting energy expenditure. Indeed, by promoting energy dissipation, beige adipocytes limit hypertrophy and associated dysfunction of white adipocytes. A few studies suggested that INSTIs could impair beiging. In agreement, we obtained preliminary data on white AT from infected macaques treated with an INSTI, DTG. We observed that the expression of several beige markers, such as PRDM16 and TMEM26 was reduced as compared to non-infected controls. To further investigate the impact of INSTIs on beiging, adipose stromal cells (ASC) isolated from the white AT of six healthy women (age: 41.7 ±2.3 years; BMI: 25.1 ±2 kg/m2) were differentiated into beige or white adipocytes. We evaluated the consequence of ASC exposition to DTG, BIC or raltegravir (RAL) on the expression of beige markers and on adipocyte functions in derived adipocytes. ASC exposed to DTG and BIC, but not RAL, exhibited a defect in beige adipocyte differentiation in favour of a white adipocyte phenotype. Indeed, INSTI treatment decreased the expression of beige adipocyte markers such as UCP1, TMEM26 and PRDM16. Both DTG and BIC also decreased the expression of FGF21, a beige adipokine, and increased the expression of leptin, more specific to white adipocytes. These alterations were associated with increased oxidative stress, and also with mitochondrial dysfunctions characterized by an impaired respiration rate evaluated by Seahorse and a lower mitochondrial uncoupling. Finally, INSTI-treatment led to increased lipid accumulation, in favour of a whitening of beige adipocytes. Altogether, these alterations could promote the emergence of hypertrophic and dysfunctional white adipocytes in response to INSTIs. Therefore, we show here, b