SAT-656 - Instis Activate Extracellular Matrix Signaling and Reprogram Erα/Pparγ to Suppress UCP1 in Thermogenic Adipocytes

Background
Integrase strand transfer inhibitor (INSTI)–based ART is linked to treatment-emergent weight gain, often greater in women. We previously showed that dolutegravir (DTG) suppresses UCP1 in thermogenic adipocytes via estrogen receptor alpha (ERα). Guided by single-nuclei RNA-seq (snRNA-seq) of human subcutaneous adipose tissue (SAT), we asked whether INSTIs activate extracellular matrix (ECM)/integrin pathways that reprogram ERα/PPARγ regulation and reduce UCP1.
Methods
SAT from people with HIV initiating bictegravir/emtricitabine/tenofovir alafenamide was profiled at baseline and 52 weeks using 10x snRNA-seq with standard quality control, participant-adjusted differential models, and pathway analyses (GO/KEGG/GSVA). For mechanistic studies, primary murine interscapular brown preadipocytes were differentiated to mature adipocytes and exposed to DTG with or without a Src-family inhibitor (PP2) or a selective HDAC3 inhibitor. Thermogenic function was quantified by Ucp1 mRNA/protein and oxygen-consumption assays. We monitored ECM/integrin activation by integrin subunit expression and phosphorylation of Src and ERK, with total controls. ERα and PPARγ phosphorylation served as an index of cofactor bias, and chromatin state at the UCP1 upstream region was evaluated by H3K27ac ChIP-qPCR.
Results
In human SAT, GSVA showed increased ECM/integrin signaling with fibronectin upregulation and decreased thermogenesis and estrogen pathway signatures at week 52 (FDR < 0.05). In murine thermogenic adipocytes, DTG reduced Ucp1 and thermogenic respiration (n≥5, p< 0.05), increased Itgav/Itgb3, and activated integrin-proximal Src with downstream ERK in a dose-responsive manner, without changes in total protein. ERα-Y537 and PPARγ-S112/S273 phosphorylation rose in parallel, a pattern classically associated with corepressor-biased control. Concordantly, H3K27ac across the UCP1 upstream region decreased by >50%, consistent with enhancer deacetylation and deactivation. PP2 normalized pathway activation and restored Ucp1 (n≥5, p< 0.05), and HDAC3 inhibition likewise prevented DTG-mediated Ucp1 suppression (n≥5, p< 0.05).
Conclusions
Human discovery and mechanistic validation converge on an ECM/integrin-initiated pathway that reprograms ERα/PPARγ, reduces acetylation at the UCP1 regulatory region, and diminishes thermogenic capacity—changes that are pharmacologically reversible. This human-anchored mechanistic signature identifies ECM/integrin signaling and HDAC3-linked chromatin control as testable steps to preserve UCP1 and metabolic function during ART.

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