PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy. Author Laura Liu, Glenn Rowe, Steven Yang, Jian Li, Federico Damilano, Mun Chan, Wenyun Lu, Cholsoon Jang, Shogo Wada, Michael Morley, Michael Hesse, Bernd Fleischmann, Joshua Rabinowitz, Saumya Das, Anthony Rosenzweig, Zoltan Arany Publication Year 2017 Type Journal Article Abstract Rationale: Pregnancy profoundly alters maternal physiology. The heart hypertrophies during pregnancy, but its metabolic adaptations are not well understood. Objective: To determine the mechanisms underlying cardiac substrate use during pregnancy. Methods and Results: We use here (13)C-glucose, (13)C-lactate, and (13)C-fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid (TCA) cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not appear altered. Insulin signaling appears intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 and GLUT4, are also unchanged. Rather, we find that the pregnancy hormone progesterone induces pyruvate dehydrogenase kinase (PDK)-4 in cardiomyocytes, and that elevated PDK4 levels in late pregnancy lead to inhibition of pyruvate dehydrogenase (PDH) and pyruvate flux into the TCA cycle. Blocking PDK4 reverses the metabolic changes seen in hearts in late pregnancy. Conclusions: Taken together, these data indicate that the hormonal environment of late pregnancy promotes metabolic remodeling in the heart at the level of PDH, rather than at the level of insulin signaling. Journal Circ Res Date Published 09/2017 ISSN Number 1524-4571 DOI 10.1161/CIRCRESAHA.117.311456 Alternate Journal Circ. Res. PMID 28928113 PubMedGoogle ScholarBibTeXEndNote X3 XML