Abstract 15626: Novel Function Annotation Tool Revealed Obesity-Induced Inflammation is Exacerbated by miR-150 Regulated B Cell Receptor Signaling

• Published in: Circulation (New York, N.Y.) N.Y.), 2023-11, Vol.148 (Suppl_1)
• Main Authors: Matz, Alyssa J, Qu, Lili, Karlinsey, Keaton, Li, Ivy, Vella, Anthony T, Aguiar, Derek, Zhou, Beiyan
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.148.suppl_1.15626

Abstract only B cells exacerbate obesity-induced metabolic dysfunction and become the second most abundant immune lineage in obese adipose tissue. However, high-resolution strategies to interrogate cellular dynamics driving B cell responses under chronic obesity stress are lacking, stifling innovative B cell-targeted therapies against obesity-induced health risk. Our previous work established the potent role of miR-150 in adipose tissue B cells’ (ATB) pro-inflammatory responses under obesity. This project aims to elucidate the mechanism of miR-150 regulated ATB actions that bolster obesity-induced inflammation. Method: We employed single-cell techniques to decipher obesity-perturbed signaling networks in B cell-specific miR-150 gain/loss of function mouse models in vivo and ex vivo . We utilized our novel B cell function annotation tool, B-RAY, to quantify B cell cytokine production, antibody secretion, and antigen presentation from single-cell RNA-Seq. These strengths permitted several key findings: Result: A) miR-150 overexpression in mature B cells alone improved systemic glucose tolerance in obesity, despite similar body adiposity. In line, miR-150 knock-out worsened glucose tolerance. B) In obese adipose tissue, B cells were skewed towards higher cytokine production and antigen presentation and away from antibody secretion compared to lean tissue. Importantly, ATBs in obesity displayed increased activity of miR-150 direct targets, Myb, Etf1, and Elk1, and reduced expression of miR-150. C) ATBs in obesity were enriched in B cell receptor (BCR) signaling and downstream cascades. miR-150 overexpression B cells exhibited reduced BCR-mediated Syk phosphorylation and calcium influx, while miR-150 knock-out yielded enhanced responses. Conclusion: These results support the hypothesis that miR-150 regulation of ATBs limits chronic inflammation in obese adipose tissue via modulating BCR signaling to prevent excessive B cell cytokine production and antigen presentation. Future work will investigate ATB actions and BCR activation in miR-150 gain/loss of function mice across time in diet-induced obesity. Collectively, this work will elucidate an important immunoregulatory network bolstering obesity-induced inflammation and health risk.