Background:
Antiretroviral therapy (ART) containing integrase strand transfer inhibitors (INSTI) has been associated with weight gain in both ART-initiation and switch studies, especially in women, but the underlying mechanisms are unclear. Estrogen promotes energy expenditure via suppressing AMP-dependent kinase (AMPK) in the hypothalamus and yet very few studies are available examining the central effects of INSTI on weight gain. Hence, we hypothesized that dolutegravir (DTG) may inhibit thermogenesis via estrogen receptors in the hypothalamus.
Methods:
We examined the effects of DTG (10mg/kg for 5 days) on food intake, energy expenditure, oxygen consumption in female mice using the Comprehensive Laboratory Animal Monitoring System. Adipose and brain tissues were analyzed using qRT-PCR and immunoblotting for appetite and thermogenesis. Primary hypothalamic neurons and inducible human pluripotent stem cells-driven hypothalamic organoids were treated with DTG and estradiol and examined for changes in cellular signaling associated with the regulation of energy homeostasis. Computational analysis was performed to evaluate the potential interaction between DTG and estrogen receptors.
Results:
We found that DTG administration to female mice reduced oxygen consumption and energy expenditure by 16% without affecting food consumption. Gene expression analyses in adipose tissues confirmed that thermogenic marker expression (UCP1, DIO2 and CIDEA) was reduced. Moreover, DTG administration activated the AMPK signaling cascade in the hypothalamus. Murine primary hypothalamic neurons treated with estrogen led to inactivation of AMPK while DTG attenuated estrogen-mediated suppression of AMPK activity. We further confirmed the DTG activates AMPK and inhibits estrogen effect on human hypothalamic organoids, which retain the heterogeneity and neural circuity of the brain. Finally, molecular docking analysis showed that DTG can physically bind to estrogen receptors.
Conclusions:
DTG administration increased body weight by suppressing energy expenditure without affecting food intake. Tissue analyses revealed that DTG activates the hypothalamic AMPK pathway, which suppresses thermogenesis. In vitro study using murine primary hypothalamic neurons and human hypothalamic organoids showed that DTG inhibits estrogen-mediated hypothalamic regulation of thermogenesis. These findings suggest a novel mechanism by which INSTIs may lead to weight gain, especially in women.
