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Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21.


ABSTRACT: Cardiac metabolism affects systemic energetic balance. Previously, we showed that Krüppel-like factor (KLF)-5 regulates cardiomyocyte PPAR? and fatty acid oxidation-related gene expression in diabetes. We surprisingly found that cardiomyocyte-specific KLF5 knockout mice (?MHC-KLF5-/-) have accelerated diet-induced obesity, associated with increased white adipose tissue (WAT). Alterations in cardiac expression of the mediator complex subunit 13 (Med13) modulates obesity. ?MHC-KLF5-/- mice had reduced cardiac Med13 expression likely because KLF5 upregulates Med13 expression in cardiomyocytes. We then investigated potential mechanisms that mediate cross-talk between cardiomyocytes and WAT. High fat diet-fed ?MHC-KLF5-/- mice had increased levels of cardiac and plasma FGF21, while food intake, activity, plasma leptin, and natriuretic peptides expression were unchanged. Consistent with studies reporting that FGF21 signaling in WAT decreases sumoylation-driven PPAR? inactivation, ?MHC-KLF5-/- mice had less SUMO-PPAR? in WAT. Increased diet-induced obesity found in ?MHC-KLF5-/- mice was absent in ?MHC-[KLF5-/-;FGF21-/-] double knockout mice, as well as in ?MHC-FGF21-/- mice that we generated. Thus, cardiomyocyte-derived FGF21 is a component of pro-adipogenic crosstalk between heart and WAT.

SUBMITTER: Pol CJ 

PROVIDER: S-EPMC6614009 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Cardiac metabolism affects systemic energetic balance. Previously, we showed that Krüppel-like factor (KLF)-5 regulates cardiomyocyte PPARα and fatty acid oxidation-related gene expression in diabetes. We surprisingly found that cardiomyocyte-specific KLF5 knockout mice (αMHC-KLF5<sup>-/-</sup>) have accelerated diet-induced obesity, associated with increased white adipose tissue (WAT). Alterations in cardiac expression of the mediator complex subunit 13 (Med13) modulates obesity. αMHC-KLF5<sup>  ...[more]

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