Abstract Body: Background: The global obesity epidemic is accompanied by a rise in cardiovascular diseases, yet its treatments can paradoxically raise disease risk. Peptide hormones are powerful regulators of energetic and hemodynamic homeostasis. While GLP1 discovery revolutionized obesity treatment, its analogs, such as semaglutide, are limited by unwanted side effects. BMP/Retinoid Acid Inducible Neural Specific 3 (BRINP3) is a gene expressed in adventitial fibroblasts that harbors genetic signals for both obesity and atherosclerotic diseases. BRP3 is a BRINP3-derived novel peptide and potent suppressant of appetite with fewer GLP1-related adverse effects and distinct cardiovascular actions.
Approach: Apoe-/- mice received daily intraperitoneal vehicle, BRP3, or semaglutide during final 4 weeks on high-fat diet. We recorded body weight, food intake, and blood pressure, and assessed aortic root lesions by histology and scRNA-seq. We treated human vascular cells with BRP3 or semaglutide for transcriptomic and functional assays.
Results: BRP3 reduced weight, blood pressure independent of weight, atherosclerotic plaque size, and plaque inflammatory cell content. Although semaglutide caused greater weight reduction, plaque size and inflammation were not significantly altered, suggesting additional BRP3-related benefits independent of weight loss. BRP3 and semaglutide elicited distinct transcriptional responses of vascular cells. BRP3 potently activated the mural cell transcriptional program in vascular SMCs that contribute to plaque formation. BRP3 robustly activated phospho-CREB signaling in mural cells and minimally in macrophages or endothelial cells. Bulk RNA-seq of acute and long-term BRP3 treatment showed extensive transcriptomic effects, while semaglutide elicited minimal changes. BRP3 altered activation of vascular SMCs, reducing their ability to recruit macrophages in transwell assays, distinct from semaglutide.
Conclusion: BRP3 is a potent suppressant of appetite and a unique ligand that directly alters vascular SMCs’ transcriptomic program, favorably altering responses to pathological triggers. BRP3 combines anorexigenic efficacy with direct, vascular mural cell-specific actions that lower blood pressure independently of weight, reduce atherosclerotic burden, and attenuate plaque inflammation, distinguishing it from GLP1R agonists. These findings suggest BRP3 as a novel cardiometabolic therapeutic agent to simultaneously treat obesity and its most dreaded sequelae.