Targeting inflammatory adipocytes in metabolic disorders: high-throughput proteomics screen identifies immunomodulatory drug repurposing candidates 9429

Abstract Description Inflammation plays a critical role in metabolic diseases, rendering generally innocuous fat-storing functions into pathological conditions such as diabetes, MASH, etc. Here, we leverage the nELISA, a novel high-throughput proteomics platform, to uncover compounds modulating the transitions between fat-storing and inflammatory adipocyte states. We treated adipocytes with free fatty acids (FFA) or IL6/TNFα and screened a library of ∼1500 well-characterized small molecules, generating 10,368 samples. Supernatants were collected and profiled with the nELISA to quantify 191 secreted proteins. IL6/TNFα treatment led to the dramatic induction of the classical adipocyte inflammatory markers IL-8 and CCL2, among dozens of regulated chemokines. Interestingly, FFA treatment regulated several of the same chemokines, but with an opposite effect, and modulated growth factors including HGF, VEGF-A/C/D, PlGF, FGF-7. As expected, prostaglandin analogs led to increased expression of inflammatory mediators in FFA treated cells, and exacerbated the effects of IL6/TNFα treatment, whereas NSAIDs had the opposite effect. Our analysis also revealed a wide range of compounds with differing MOAs regulating the transitions between normal and inflammatory states, highlighting potential avenues for therapeutic intervention. We will discuss novel targets for immunometabolic interventions, as well as the broader potential of the nELISA for high-throughput screens in immune-related settings. Topic Categories Immune Mechanisms of Human Disease (HUM)