Loss of protein kinase D activity reveals redundancy in cardiac glucose metabolism and preserves cardiac function in obesity

Kirstie A. De Jong, Liam G. Hall, Mark C. Renton, Tim Connor, ... Sean L. McGee


Protein kinase D (PKD) signalling has been implicated in stress-induced cardiac remodelling and function, as well as metabolic processes including contraction-mediated cardiac glucose uptake. More recently, PKD has emerged as a nutrient sensing kinase that is activated in high-lipid environments, such as in obesity. However, the role of PKD signalling in cardiac glucose metabolism and in cardiac function, in both normal and obese conditions, remains unknown.


A cardiac-specific and inducible dominant negative (DN) PKD mouse model was developed. Echocardiography was used to assess cardiac function, while metabolic phenotyping was performed, including stable isotope metabolomics on cardiac tissue, in mice fed either regular chow, or a high fat diet (43% calories from fat).


Cardiac PKD activity was reduced by ∼90%, following DN PKD induction in adult mice. These mice had impaired basal cardiac glucose clearance, suggesting impaired contraction-mediated glucose uptake, but normal cardiac function. In obesity studies, indices of systolic function were reduced in Control mice, but not in cardiac DN PKD mice. Using targeted stable isotope metabolomics analyses, no differences in glucose flux through glycolysis or the TCA cycle were observed between groups.


These data show that PKD contributes to cardiac dysfunction in obesity and highlight the redundancy in cardiac glucose metabolism that maintain cardiac glucose flux in vivo. These data suggest that impairments in contraction-mediated glucose uptake are unlikely to drive cardiac dysfunction in both normal and metabolic disease states.