Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1865; no. 9; pp. 2125 - 2137
• Main Authors: Pol, Christine J., Pollak, Nina M., Jurczak, Michael J., Zacharia, Effimia, Karagiannides, Iordanes, Kyriazis, Ioannis D., Ntziachristos, Panagiotis, Scerbo, Diego A., Brown, Brett R., Aifantis, Iannis, Shulman, Gerald I., Goldberg, Ira J., Drosatos, Konstantinos
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.09.2019
• Subjects: Adipose Tissue, White - metabolism; Adipose Tissue, White - pathology; Animals; Body Weight; Diet, High-Fat; Female; FGF21; Fibroblast Growth Factors - blood; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Heart; High fat diet; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Krüppel-like factor; Leptin - blood; Male; Mediator Complex - genetics; Mediator Complex - metabolism; Mice; Mice, Knockout; MicroRNAs - metabolism; Myocardium - metabolism; Myocytes, Cardiac - cytology; Myocytes, Cardiac - metabolism; Obesity; Obesity - etiology; Signal Transduction; Heart; Obesity; ANP; SUMO; KLF; BNP; HFD; DIO; WAT; 18S; RXR; Snord65; Actb; High fat diet; MED13; BAT; FAO; Rplp0; Krüppel-like factor; FGF21
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2019.04.010

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−/−) 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−/− 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 αMHC-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 PPARγ inactivation, αMHC-KLF5−/− mice had less SUMO-PPARγ in WAT. Increased diet-induced obesity found in αMHC-KLF5−/− mice was absent in αMHC-[KLF5−/−;FGF21−/−] double knockout mice, as well as in αMHC-FGF21−/− mice that we generated. Thus, cardiomyocyte-derived FGF21 is a component of pro-adipogenic crosstalk between heart and WAT. [Display omitted] •Cardiomyocyte-specific KLF5 deletion accelerates diet-induced obesity.•KLF5 is a positive regulator of Med13 expression.•The proadipogenic effect of KLF5 relies also on non-MED13 mechanisms.•Cardiomyocyte KLF5 regulates systemic metabolism and adiposity via FGF21.