Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1865

Article

Pol, Christine J.¹  Pollak, Nina M.^2,8,9  Jurczak, Michael J.^3,10  Zacharia, Effimia¹  Karagiannides, Iordanes^4,5  Kyriazis, Ioannis D.¹  Ntziachristos, Panagiotis^6,11,12  Scerbo, Diego A.^7,13  Brown, Brett R.¹  Aifantis, Iannis⁶  Shulman, Gerald I.³  Goldberg, Ira J.^7,14  Drosatos, Konstantinos¹ 

[1] Temple Univ, Lewis Katz Sch Med, Metab Biol Lab, Ctr Translat Med,Dept Pharmacol, Philadelphia, PA 19122 USA

[2] Karl Franzens Univ Graz, Inst Mol Biosci, Graz, Austria

[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06510 USA

[4] Univ Calif Los Angeles, David Geffen Sch Med, Ctr Inflammatory Bowel Dis, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Neuroendocrine Assay Core, Los Angeles, CA 90095 USA

[6] NYU, Sch Med, Dept Pathol, Howard Hughes Med Inst, New York, NY USA

[7] Columbia Univ, Div Prevent Med & Nutr, New York, NY 10032 USA

[8] Univ Sunshine Coast, Sch Sci & Engn, Genecol Res Ctr, Sippy Downs, Qld, Australia

[9] Univ Queensland, CSIRO Synthet Biol Future Sci Platform, Australian Inst Bioengn & Nanotechnol, Sch Chem & Mol Biosci, Brisbane, Qld, Australia

[10] Univ Pittsburgh, Sch Med, Dept Med, Div Endocrinol & Metab, Pittsburgh, PA 15213 USA

[11] Northwestern Univ, Dept Biochem & Mol Genet, Chicago, IL 60611 USA

[12] Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA

[13] Univ Iowa, Dept Biochem, Carver Coll Med, Iowa City, IA 52242 USA

[14] NYU, Div Endocrinol Diabet & Metab, Langone Sch Med, New York, NY USA

关键词: Kruppel-like factor;    FGF21;    Heart;    Obesity;    High fat diet;   

DOI  :  10.1016/j.bbadis.2019.04.010

来源: Elsevier

【 摘 要 】

Cardiac metabolism affects systemic energetic balance. Previously, we showed that Kriippel-like factor (KLF)-5 regulates cardiomyocyte PPAR alpha and fatty acid oxidation-related gene expression in diabetes. We surprisingly found that cardiomyocyte-specific KLF5 knockout mice (alpha MEIC-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. alpha 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 alpha 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 gamma inactivation, alpha MHC-KLF5(-/-) mice had less SUMO-PPAR gamma in WAT. Increased diet-induced obesity found in aMHC-KLF5-/- mice was absent in alpha MHC-[KLF5(-/-);FGF21(-/-)] double knockout mice, as well as in alpha MHC-FGF21(-/-) mice that we generated. Thus, cardiomyocyte-derived FGF21 is a component of pro-adipogenic crosstalk between heart and WAT.

【 授权许可】

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