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Circ Res. 2017 Dec 8;121(12):1370-1378. doi: 10.1161/CIRCRESAHA.117.311456. Epub 2017 Sep 19.

PDK4 Inhibits Cardiac Pyruvate Oxidation in Late Pregnancy.

Author information

1
From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA (L.X.L., F.D.); Corrigan Minehan Heart Center, Massachusetts General Hospital, Boston (L.X.L., F.D., M.C.C., S.D., A.R.); Division of Cardiovascular Disease, University of Alabama at Birmingham (G.C.R.); Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.Y., J.L., S.W., M.M., Z.A.); Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ (W.L., C.J., J.D.R.); and Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Germany (M.H., B.K.F.).
2
From the Cardiovascular Institute, Beth Israel Deaconess Medical Center, Boston, MA (L.X.L., F.D.); Corrigan Minehan Heart Center, Massachusetts General Hospital, Boston (L.X.L., F.D., M.C.C., S.D., A.R.); Division of Cardiovascular Disease, University of Alabama at Birmingham (G.C.R.); Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia (S.Y., J.L., S.W., M.M., Z.A.); Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ (W.L., C.J., J.D.R.); and Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Germany (M.H., B.K.F.). zarany@mail.med.upenn.edu.

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.

KEYWORDS:

glucose; heart; metabolism; mitochondria; pregnancy; progesterone

PMID:
28928113
PMCID:
PMC5722682
[Available on 2018-12-08]
DOI:
10.1161/CIRCRESAHA.117.311456
[Indexed for MEDLINE]

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