Reversible Effects of Integrase Inhibitors on Newly Differentiated Adipocytes

Weight gain has been associated with integrase strand transfer inhibitors (INSTIs) in real-world studies; however, the causality of this relationship is unclear. Thus, we examined the effects of the INSTI, Dolutegravir (DTG), on human adipose cells in vitro and the reversibility of these effects by switching to a protease inhibitor, Darunavir (DRV). We established cultures of human adipose stem cells (ASCs) and newly differentiated adipocytes from individuals without HIV. For adipocytes, cells were exposed to DTG or DRV for 7 days, after which cells were maintained or switched to another ART. Experiments examining ASCs and the effects on adipogenesis initiated exposure during proliferation and continued throughout differentiation. Adipogenic outcomes included triglyceride content, gene expression, and adipokine secretion. Metabolic outcomes included lactate production, lipolysis, and oxygen consumption rates. DTG suppressed the secretion of adiponectin and leptin, and this was reversed following the switch to DRV in adipocytes without the altered expression of adipogenic genes. DTG exposure increased markers of endoplasmic reticulum stress, elevated lactate production, and suppressed oxygen consumption in ASCs. Exposure to DTG during differentiation lowered triglyceride accumulation and adiponectin secretion without altering the expression of adipogenic markers. Thus, DTG exposure resulted in changes in adipocyte function consistent with the progression of metabolically adverse phenotypes, and these effects were reversible.