# Defining cellular and molecular processes underlying adipose tissue dysfunction onINSTI-based antiretroviral therapy > **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $707,929 ## Abstract PROJECT SUMMARY/ABSTRACT The introduction of the integrase strand transfer inhibitor (INSTI) class of HIV drugs transformed the treatment of persons with HIV (PWH), offering highly effective and well-tolerated options with fewer drug interactions. However, concerns about INSTIs causing weight gain, particularly in women, have been raised in various studies. Despite recent investigations, a definitive explanation for the mechanism behind INSTI-associated weight gain remains elusive. Recently, we reported that the administration of dolutegravir led to an increase in fat mass and body weight through suppression of thermogenic processes in a rodent model, which was associated with a disruption of mitochondrial respiration and reduced expression of uncoupling protein1 (UCP1) in adipose tissues. Moreover, other groups further confirmed these results using non-human primates (NHPs) infected with SIV. Interestingly, it has been well-documented that estrogen plays a critical role in promoting thermogenic processes through the peripheral and central nervous systems. Our preliminary data shows that dolutegravir inhibits estrogen signaling action, and genetic deletion of estrogen receptors in adipocytes attenuates dolutegravir- mediated suppression of the thermogenic process. Based on these observations, we hypothesize that dolutegravir reduces energy expenditure via disrupting estrogen action in adipocytes, leading to the weight gain associated with INSTIs. To further investigate this hypothesis, we will first define the molecular mechanisms by which INSTI-based ART disrupts whole-body metabolism and leads to weight gain via the estrogen receptor (ER) using a transgenic mouse model in which ER is genetically deleted in adipose tissues. We will perform biochemical and molecular analyses combined with multi-omics approaches, including single-cell RNA and ATAC-sequencing to further elucidate the molecular network associated with INSTI-related adipose function disruption via ER (Aim 1). Next, to address the absence of a chronic retroviral infection in a murine model, we will investigate how estrogen affects INSTI-based ART-mediated weight gain over time via disrupted thermogenesis in NHPs infected with SIV and ovariectomized with or without estrogen replacement. We will also perform temporal transcriptomic analyses on adipose tissues to gain a comprehensive understanding of how these tissues are altered through infection, ART initiation, and E2 manipulation over time (Aim 2). Finally, we will evaluate the effects of INSTI-based ART on thermogenic pathways and mitochondria functions in adipose tissue at multiple time points from PWH starting INSTI-based treatment and followed for one year. Moreover, we will perform integrative transcriptomics analyses utilizing cross-species omics data (Aim 3). These multidisciplinary and translational works will shed light on how INSTIs contribute to weight gain, especially in females, and inform the development of new strategi... ## Key facts - **NIH application ID:** 11020626 - **Project number:** 1R01DK141455-01 - **Recipient organization:** JOHNS HOPKINS UNIVERSITY - **Principal Investigator:** TODD T BROWN - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $707,929 - **Award type:** 1 - **Project period:** 2024-09-10 → 2029-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/11020626 ## Citation > US National Institutes of Health, RePORTER application 11020626, Defining cellular and molecular processes underlying adipose tissue dysfunction onINSTI-based antiretroviral therapy (1R01DK141455-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11020626. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*