Adipose tissue expression of HuR modulates cardiac pathology via adipose tissue-derived extracellular vesicles.

Obesity is widely associated with increased cardiovascular disease (CVD) extending beyond common co-morbidities such as dyslipidemia and diabetes, as evidenced by increased CVD risk in 'metabolically healthy obese' individuals. Adipose tissue serves a broad role as an endocrine organ and has been shown to have a multitude of effects on cardiac physiology depending on metabolic state, adipose depot location, and primary cell type. We have previously shown that adipose tissue-specific deletion of HuR (Adipo-HuR ) reduces BAT-mediated adaptive thermogenesis, accompanied by the spontaneous development of cardiac hypertrophy and fibrosis in mice. We and others have also shown that expression of HuR in subcutaneous white adipose tissue (scWAT) is decreased in obesity, suggesting a potential mechanistic link between obesity, HuR expression in scWAT, and CVD. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) across both cardiac and adipose tissue (BAT, scWAT, and perigonadal WAT) to correlate adipose tissue gene expression with the phenotype of cardiac fibrosis. Our results suggest HuR-dependent adipose tissue-derived extracellular vesicles (Ad-EVs) as the mediator of cardiac pathology. To provide functional evidence for the role of Ad-EVs in driving cardiac pathology in Adipo-HuR mice, we demonstrate that plasma-isolated vesicles from Adipo-HuR mice, but not wild-type littermate controls, induced a significant increase in hypertrophic signaling in primary isolated mouse cardiomyocytes. In conclusion, our results demonstrate that loss of HuR expression in adipose tissue, as observed in the setting of obesity, is sufficient to induce cardiac hypertrophy and fibrosis, in part through endocrine-mediated Ad-EV signaling.