PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

TitlePDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.
Publication TypeJournal Article
Year of Publication2017
AuthorsLiu, LX, Rowe, GC, Yang, S, Li, J, Damilano, F, Chan, MChun, Lu, W, Jang, C, Wada, S, Morley, M, Hesse, M, Fleischmann, BK, Rabinowitz, JD, Das, S, Rosenzweig, A, Arany, Z
JournalCirc Res
Volume121
Issue12
Pagination1370-1378
Date Published2017 Dec 08
ISSN1524-4571
KeywordsAnimals, Citric Acid Cycle, Fatty Acids, Female, Glucose, Lactic Acid, Mice, Mice, Inbred C57BL, Myocardium, Pregnancy, Progesterone, Protein-Serine-Threonine Kinases, Pyruvic Acid
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 13C glucose, 13C lactate, and 13C fatty acid tracing analyses to show that hearts in late pregnant mice increase fatty acid uptake and oxidation into the tricarboxylic acid cycle, while reducing glucose and lactate oxidation. Mitochondrial quantity, morphology, and function do not seem altered. Insulin signaling seems intact, and the abundance and localization of the major fatty acid and glucose transporters, CD36 (cluster of differentiation 36) and GLUT4 (glucose transporter type 4), are also unchanged. Rather, we find that the pregnancy hormone progesterone induces PDK4 (pyruvate dehydrogenase kinase 4) in cardiomyocytes and that elevated PDK4 levels in late pregnancy lead to inhibition of PDH (pyruvate dehydrogenase) and pyruvate flux into the tricarboxylic acid 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.

DOI10.1161/CIRCRESAHA.117.311456
Alternate JournalCirc. Res.
PubMed ID28928113
PubMed Central IDPMC5722682
Grant ListR01 DK107667 / DK / NIDDK NIH HHS / United States
R01 HL094499 / HL / NHLBI NIH HHS / United States
R01 HL126797 / HL / NHLBI NIH HHS / United States
F31 AG041598 / AG / NIA NIH HHS / United States
P30 DK019525 / DK / NIDDK NIH HHS / United States