2054-LB: Mitigating Adipose Tissue Dysfunction and Insulin Resistance in Obesity via SVEP1 Peptide-Mediated Suppression of Adipose Tissue Macrophage-Induced Inflammation

Introduction: Adipose tissue dysfunction in obesity poses a critical threat, causing metabolic impairment and systemic inflammation. This study explores the therapeutic potential of a peptide from SVEP1, targeting its integrin α9β1 receptor, to alleviate obesity-induced adipose dysfunction and insulin resistance by reducing pro-inflammatory macrophage activity. Methods: We comprehensively examined the peptide's effect on adipose tissue dysfunction using in silico predictive binding, LPS-activated mono and co-culture cell systems, and diet-induced obese mice. Results: Analysis of integrin α9β1 revealed specific expression in myeloid cells, particularly dysfunctional adipose tissue macrophages. In silico predictions confirmed the peptide's integrin affinity and ability to block ligand interactions. Peptide-treated LPS-activated BMDM exhibited reduced adhesion and mobility on decellularized matrices from adipocytes. The peptide suppressed pro-inflammatory activation, by inhibiting the MAPK and NF-κB pathways, altered transcriptomics, and reduced cytokine production in ex vivo isolated adipose tissue macrophages. Epididymal adipose tissue peptide administration in diet-induced obese mice reduced body and tissue weight, improved glucose sensitivity, hepatic function, and lessened adipose inflammation through modulated macrophage phenotype. Bulk and single-cell transcriptomics indicated decreased pro-inflammatory responses, improving adipocyte status, insulin sensitivity, and thermogenic capacity due to the anti-inflammatory state of tissue macrophages and upregulated mitochondrial activity. Conclusions: The SVEP1-derived peptide emerges as a regulator of macrophages in obesity, effectively mitigating inflammation and restoring glucose homeostasis. This study offers insights into potential therapeutic avenues for addressing adipose tissue dysfunction.