Enhanced insulin‐responsive AS160 elicits cardioprotection during metabolic stress

Heart disease is the leading cause of death in the United States, and cardiovascular mortality rates positively correlate with the presence of diabetes and metabolic syndrome. There is a consensus that abdominal obesity is a major driver in the pathogenesis of metabolic syndrome, with severe adverse effects on cardiovascular risk factors. In the midst of a growing recognition of the effect of adipose tissue dysfunction and adipokine imbalance on cardiovascular disease, a less‐well understood mechanism is the effect of cardiac metabolism and function on systemic metabolic homeostasis. There is increasing recognition that signals produced by the heart can affect distant organ function; however, little is known regarding mechanistic links. While elevated GRK2 activity and expression occur early in cardiovascular disease and contribute to progression, ongoing studies show cardiac restricted expression of a short, amino terminal fragment of GRK2 (βARKnt) preserves cardiac structure and function during chronic pressure overload. Surprisingly, these studies revealed a significant decrease in gonadal fat weight, equivalent to human abdominal fat, in male βARKnt mice at baseline and following cardiac stress. In contrast, cardiac overexpression of GRK2 produces an overall lean phenotype, while the peptide inhibitor of GRK2 (βARKct) enhances the obesogenic phenotype. Proteomic analysis to identify βARKnt binding partners that may underlie the improved cardiovascular and metabolic phenotype uncovered a selective functional interaction of both endogenous GRK2 and βARKnt with AKT substrate of 160kDa (AS160). AS160 has emerged as a key downstream regulator of insulin signaling, integrating physiological and metabolic cues to couple energy demand to membrane recruitment of Glut4. Our preliminary data indicate that in βARKnt mice, cardiomyocyte insulin sensitivity is improved during stress, without metabolic switching. These mice demonstrate an ~23% increase in phosphorylated Akt, ~75% increase in phosphorylated and total AS160, and upregulation of the mTORC1 pathway. Seahorse of dissociated adult cardiomyocytes and Oroboros of fresh, permeabilized cardiac tissue exhibited enhanced spare respiratory activity and ATP production in the presence of glucose and palmitate. Unlike control mice that develop insulin resistance in response to high fat diet stress, the βARKnt mice demonstrate enhanced glucose tolerance and improved insulin sensitivity (glucose tolerance test area under curve (AUC) is 2958 vs 2354; insulin tolerance AUC is 1245 vs 991.7 at 14 weeks), increased energy expenditure, and enhanced cardiac function at 4 and 14 weeks. These data suggest that the enhanced AS160‐mediated signaling in the βARKnt mice may ameliorate pathological cardiac remodeling through direct modulation of insulin signaling within cardiomyocytes, and translate these to beneficial effects on systemic metabolism. Ongoing studies seek to elucidate the underlying mechanisms of these beneficial effects, to gain insights into development of new therapeutic strategies for metabolic syndrome and obesity‐related cardiovascular disease.