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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 myocyte KLF5 regulates body weight via alteration of cardiac FGF21.

Pol Christine J CJ Pollak Nina M NM Jurczak Michael J MJ Zacharia Effimia E Karagiannides Iordanes I Kyriazis Ioannis D ID Ntziachristos Panagiotis P Scerbo Diego A DA Brown Brett R BR Aifantis Iannis I Shulman Gerald I GI Goldberg Ira J IJ Drosatos Konstantinos K

Biochimica et biophysica acta. Molecular basis of disease 20190426 9

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]

PMID: 31029826

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Project description:Objectivec-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood.MethodsWe generated liver-specific c-Jun knock-out (c-jun△li) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature. Primary hepatocytes were also used to explore a direct regulation of c-Jun in gluconeogenesis.Resultsc-jun△li mice showed higher hepatic gluconeogenic capacity compared with control mice, and similar results were obtained in vitro. In addition, fibroblast growth factor 21 (FGF21) expression was directly inhibited by c-Jun knockdown and adenovirus-mediated hepatic FGF21 over-expression blocked the effect of c-Jun on gluconeogenesis in c-jun△li mice. Interestingly, c-jun△li mice also exhibited higher body temperature, with induced thermogenesis and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). Furthermore, the body temperature became comparable between c-jun△li and control mice at thermoneutral temperature (30 °C). Moreover, the activity of sympathetic nervous system (SNS) was increased in c-jun△li mice and the higher body temperature was inhibited by beta-adrenergic receptor blocker injection. Finally, the activated SNS and increased body temperature in c-jun△li mice was most likely caused by the signals from the brain and hepatic vagus nerve, as the expression of c-Fos (the molecular marker of neuronal activation) was changed in several brain areas controlling body temperature and body temperature was decreased by selective hepatic vagotomy.ConclusionsThese data demonstrate a novel function of hepatic c-Jun in the regulation of gluconeogenesis and body temperature via FGF21 and neural signals. Our results also provide novel insights into the organ crosstalk in the regulation of the whole-body physiology.

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

Publications

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

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