Subcutaneous white adipose tissue expression of HuR mediates cardiac pathology via adipose tissue-derived extracellular vesicles

Abstract

Obesity is a rapidly growing epidemic worldwide, especially in the United States, and is associated with cardiovascular disease (CVD), diabetes, cancer, and a multitude of other comorbidities. Adipose tissue has been shown to act as an endocrine organ in the body and to mediate cardiac physiology. We have previously shown that deletion of HuR specifically in adipocytes (Adipo-HuR KO) induces cardiac fibrosis in mice, independent of traditional adipose/obesity co-morbidities (dyslipidemia, hypertension, diabetes).​ Deletion of HuR in the adipocyte affects both brown adipose tissue (BAT) depots as well as subcutaneous white adipose tissue (scWAT) depots. We have shown that HuR deletion in BAT (using a UCP1-driven cre model) maintains normal cardiac function compared to Adipo-HuR KO mice. This points toward scWAT being the primary mediator of cardiac pathology from adipose tissue, which is consistent with our previously published bioinformatic analysis suggesting HuR-dependent adipose tissue-derived extracellular vesicles (Ad-EVs) as the mechanism by which this occurs.The goal of this work is to identify the mechanisms by which HuR expression in subcutaneous white adipose tissue (scWAT) mediates cardiac function via Ad-EVs. Here, we show that Ad-EVs isolated from scWAT depots of our Adipo-HuR KO model induce significant hypertrophic signaling in vitro, compared to wild-type littermates. We also show that expression of HuR in scWAT specifically is decreased with obesity and age, suggesting a potential mechanistic link between obesity, HuR expression in scWAT, and CVD.In conclusion, our results demonstrate that loss of HuR expression in scWAT is sufficient to induce cardiac hypertrophy and fibrosis, in part through endocrine-mediated Ad-EV signaling. In addition, we are beginning to identify HuR-dependent gene expression patterns in human scWAT which may potentially play a significant role in this signaling axis. This work was supported by NIH grants R01-HL132111 and HL158671 (MT). RD is supported by a Peter Lauf Travel Award from the Ohio Physiological Society. SP is supported by an NIH Training grant T32HL125204 (PIs: Molkentin and Kranias). ARG was supported by American Heart Association Predoctoral Fellowship (916812). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.