Reversible Effects of Integrase Inhibitors on Newly Differentiated Adipocytes.

Area of Science:

• Biochemistry
• Cell Biology
• Endocrinology

Background:

• Weight gain is linked to integrase strand transfer inhibitors (INSTIs) in real-world studies, but causality remains unclear.
• Dolutegravir (DTG) is an INSTI commonly used in HIV treatment.
• Investigating the direct effects of DTG on human adipose cells is crucial for understanding potential metabolic side effects.

Purpose of the Study:

• To examine the in vitro effects of Dolutegravir (DTG) on human adipose stem cells (ASCs) and differentiated adipocytes.
• To assess the reversibility of DTG-induced changes by switching to Darunavir (DRV), a protease inhibitor.
• To elucidate the impact of DTG on adipogenesis, adipokine secretion, and cellular metabolism.

Main Methods:

• Human ASCs and adipocytes were cultured and exposed to DTG or DRV.
• Cells were assessed for adipogenic outcomes (triglyceride content, gene expression, adipokine secretion).
• Metabolic parameters including lactate production, lipolysis, and oxygen consumption were measured.

Main Results:

• DTG suppressed adiponectin and leptin secretion in adipocytes, an effect reversed by switching to DRV.
• DTG exposure increased endoplasmic reticulum stress markers and lactate production, while suppressing oxygen consumption in ASCs.
• DTG reduced triglyceride accumulation and adiponectin secretion during adipocyte differentiation without altering key adipogenic gene expression.

Conclusions:

• DTG exposure induces functional changes in human adipose cells consistent with adverse metabolic phenotypes.
• These DTG-induced effects on adipocyte function are reversible upon switching to DRV.
• The findings suggest a potential cellular mechanism linking INSTI use to metabolic alterations, highlighting the importance of reversibility.