Obesity has been 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. However, a full understanding of the mechanisms that drive this
association remains an unmet need. 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 (e.g visceral vs. subcutaneous), and primary cell type (e.g. brown vs. white). As such, the long-term
goals of my laboratory are to increase our mechanistic understanding of adipose tissue-derived endocrine
signaling to the myocardium and specifically how it is impacted by (1) brown adipose tissue (BAT)-mediated
energy expenditure and (2) changes in adipose tissue homeostasis.
To this end, we have recently identified the RNA binding protein HuR as a novel mediator of the adipose-
cardiac signaling axis and have shown decreased HuR expression in subcutaneous WAT (scWAT) from obese
mice and humans corresponds with decreased cardiac function. Specifically, we recently showed that
adipocyte-specific deletion of HuR in mice (Adipo-HuR-/-) leads to a deficiency of BAT-mediated thermogenic
metabolism, which is strongly associated with cardiovascular health, and is sufficient to induce cardiac
hypertrophy and fibrosis. Preliminary data suggests that this cardiac pathology is driven by HuR-dependent
adipose-derived extracellular vesicles (Ad-EVs).
Our central hypothesis is that decreased HuR expression in adipose tissue contributes to cardiac
pathology through disruption of adaptive thermogenesis and Ad-EV mediated endocrine signaling.
Aim 1 will elucidate the mechanisms by which HuR mediates calcium cycling in BAT and the functional
contribution of these HuR-dependent pathways to thermogenic metabolism. The working hypothesis is that
HuR mediates thermogenesis in BAT through regulation of calcium (Ca2+) cycling. Aim 2 will delineate the
functional role of HuR-dependent Ad-EVs on cardiac hypertrophy and identify the translational link between
HuR activity and gene expression in human adipose tissue and cardiac function. The working hypothesis is
that the loss of HuR expression in adipose tissue, either through genetic deletion or obesity, mediates a pro-
hypertrophic endocrine signaling to the myocardium via Ad-EVs.
This work is timely and innovative given our recent publications, the association of BAT activity with
cardiovascular health in humans, and findings from Scherer and colleagues showing that large circulating EVs
from adipocytes directly impact cardiomycotyes in vivo. Our results will increase our mechanistic
understanding of (1) HuR as a mediator of thermogenesis via Ca2+ cycling, (2) adipose tissue signaling to the
myocardium, and (3) the translational link between adipose tissue gene expression and cardiac function.
