Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

Christine J. Pol; Nina M. Pollak; Michael J. Jurczak; Effimia Zacharia; Iordanes Karagiannides; Ioannis D. Kyriazis; Panagiotis Ntziachristos; Diego A. Scerbo; Brett R. Brown; Iannis Aifantis; Gerald I. Shulman; I. J. Goldberg; Konstantinos Drosatos

doi:10.1016/j.bbadis.2019.04.010

Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

Christine J. Pol, Nina M. Pollak, Michael J. Jurczak, Effimia Zacharia, Iordanes Karagiannides, Ioannis D. Kyriazis, Panagiotis Ntziachristos, Diego A. Scerbo, Brett R. Brown, Iannis Aifantis, Gerald I. Shulman, I. J. Goldberg, Konstantinos Drosatos^*

^*Corresponding author for this work

Biochemistry and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	2125-2137
Number of pages	13
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1865
Issue number	9
DOIs	https://doi.org/10.1016/j.bbadis.2019.04.010
State	Published - Sep 1 2019

Funding

This work was supported by NHLBI “Pathway to Independence” K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur Förderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute ( R00CA188293-02 ), the American Society of Hematology , the Leukemia Research Foundation , the St. Baldrick's Foundation , and the Zell Foundation (P.N.), the “Stavros Niarchos Foundation”-RTP-CEM fellowship by the World Hellenic Biomedical Association -WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation , the Leukemia & Lymphoma Society , the Ralph S. French Charitable Foundation Trust , the Chemotherapy Foundation , the V Foundation for Cancer Research , the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. We would like to thank Mesele C. Valenti for technical assistance. The graphical abstract was produced using Servier Medical Art (http://www.servier.com). Conceptualization K.D. C.J.P.; Methodology, K.D. C.J.P. N.M.P. M.J.J. E.Z. I.D.K. P.N.; Validation, C.J.P. N.M.P.; Formal Analysis, C.J.P. N.M.P. M.J.J. E.Z. I.D.K. I.K.; Investigation, C.J.P, N.M.P. M.J.J. E.Z. I.K. I.D.K. D.A.S, B.R.B. and K.D.; Resources, K.D. I.J.G. G.I.S. I.A.; Writing ? Original Draft, C.J.P. K.D.; Writing ? Review & Editing, C.J.P. N.M.P. M.J.J. E.Z. I.K. I.D.K. P.N. I.A. G.I.S. I.J.G. K.D.; Supervision K.D.; Project administration, C.J.P. K.D.; Funding Acquisition, K.D, I.J.G. I.A. P.N. This work was supported by NHLBI ?Pathway to Independence? K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur F?rderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, and the Zell Foundation (P.N.), the ?Stavros Niarchos Foundation?-RTP-CEM fellowship by the World Hellenic Biomedical Association-WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. We would like to thank Mesele C. Valenti for technical assistance. The graphical abstract was produced using Servier Medical Art (http://www.servier.com). Conceptualization K.D. C.J.P.; Methodology, K.D. C.J.P. N.M.P. M.J.J. E.Z. I.D.K. P.N.; Validation, C.J.P. N.M.P.; Formal Analysis, C.J.P. N.M.P. M.J.J. E.Z. I.D.K. I.K.; Investigation, C.J.P, N.M.P. M.J.J. E.Z. I.K. I.D.K. D.A.S, B.R.B. and K.D.; Resources, K.D. I.J.G. G.I.S. I.A.; Writing – Original Draft, C.J.P. K.D.; Writing – Review & Editing, C.J.P. N.M.P. M.J.J. E.Z. I.K. I.D.K. P.N. I.A. G.I.S. I.J.G. K.D.; Supervision K.D.; Project administration, C.J.P. K.D.; Funding Acquisition, K.D, I.J.G. I.A. P.N. This work was supported by NHLBI “Pathway to Independence” K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur Förderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, and the Zell Foundation (P.N.), the “Stavros Niarchos Foundation”-RTP-CEM fellowship by the World Hellenic Biomedical Association-WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist.

Keywords

FGF21
Heart
High fat diet
Krüppel-like factor
Obesity

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbadis.2019.04.010

Cite this

Pol, C. J., Pollak, N. M., Jurczak, M. J., Zacharia, E., Karagiannides, I., Kyriazis, I. D., Ntziachristos, P., Scerbo, D. A., Brown, B. R., Aifantis, I., Shulman, G. I., Goldberg, I. J., & Drosatos, K. (2019). Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1865(9), 2125-2137. https://doi.org/10.1016/j.bbadis.2019.04.010

@article{d1a6bb8fc1b2479dbf543d5f905ba246,

title = "Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21",

abstract = "Cardiac metabolism affects systemic energetic balance. Previously, we showed that Kr{\"u}ppel-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.",

keywords = "FGF21, Heart, High fat diet, Kr{\"u}ppel-like factor, Obesity",

author = "Pol, {Christine J.} and Pollak, {Nina M.} and Jurczak, {Michael J.} and Effimia Zacharia and Iordanes Karagiannides and Kyriazis, {Ioannis D.} and Panagiotis Ntziachristos and Scerbo, {Diego A.} and Brown, {Brett R.} and Iannis Aifantis and Shulman, {Gerald I.} and Goldberg, {I. J.} and Konstantinos Drosatos",

note = "Funding Information: This work was supported by NHLBI “Pathway to Independence” K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur F{\"o}rderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute ( R00CA188293-02 ), the American Society of Hematology , the Leukemia Research Foundation , the St. Baldrick's Foundation , and the Zell Foundation (P.N.), the “Stavros Niarchos Foundation”-RTP-CEM fellowship by the World Hellenic Biomedical Association -WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation , the Leukemia & Lymphoma Society , the Ralph S. French Charitable Foundation Trust , the Chemotherapy Foundation , the V Foundation for Cancer Research , the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. Funding Information: We would like to thank Mesele C. Valenti for technical assistance. The graphical abstract was produced using Servier Medical Art (http://www.servier.com). Conceptualization K.D. C.J.P.; Methodology, K.D. C.J.P. N.M.P. M.J.J. E.Z. I.D.K. P.N.; Validation, C.J.P. N.M.P.; Formal Analysis, C.J.P. N.M.P. M.J.J. E.Z. I.D.K. I.K.; Investigation, C.J.P, N.M.P. M.J.J. E.Z. I.K. I.D.K. D.A.S, B.R.B. and K.D.; Resources, K.D. I.J.G. G.I.S. I.A.; Writing ? Original Draft, C.J.P. K.D.; Writing ? Review & Editing, C.J.P. N.M.P. M.J.J. E.Z. I.K. I.D.K. P.N. I.A. G.I.S. I.J.G. K.D.; Supervision K.D.; Project administration, C.J.P. K.D.; Funding Acquisition, K.D, I.J.G. I.A. P.N. This work was supported by NHLBI ?Pathway to Independence? K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur F?rderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, and the Zell Foundation (P.N.), the ?Stavros Niarchos Foundation?-RTP-CEM fellowship by the World Hellenic Biomedical Association-WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. Funding Information: We would like to thank Mesele C. Valenti for technical assistance. The graphical abstract was produced using Servier Medical Art (http://www.servier.com). Conceptualization K.D. C.J.P.; Methodology, K.D. C.J.P. N.M.P. M.J.J. E.Z. I.D.K. P.N.; Validation, C.J.P. N.M.P.; Formal Analysis, C.J.P. N.M.P. M.J.J. E.Z. I.D.K. I.K.; Investigation, C.J.P, N.M.P. M.J.J. E.Z. I.K. I.D.K. D.A.S, B.R.B. and K.D.; Resources, K.D. I.J.G. G.I.S. I.A.; Writing – Original Draft, C.J.P. K.D.; Writing – Review & Editing, C.J.P. N.M.P. M.J.J. E.Z. I.K. I.D.K. P.N. I.A. G.I.S. I.J.G. K.D.; Supervision K.D.; Project administration, C.J.P. K.D.; Funding Acquisition, K.D, I.J.G. I.A. P.N. This work was supported by NHLBI “Pathway to Independence” K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur F{\"o}rderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, and the Zell Foundation (P.N.), the “Stavros Niarchos Foundation”-RTP-CEM fellowship by the World Hellenic Biomedical Association-WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V.",

year = "2019",

month = sep,

day = "1",

doi = "10.1016/j.bbadis.2019.04.010",

language = "English (US)",

volume = "1865",

pages = "2125--2137",

journal = "Biochimica et Biophysica Acta - Molecular Basis of Disease",

issn = "0925-4439",

publisher = "Elsevier B.V.",

number = "9",

}

Pol, CJ, Pollak, NM, Jurczak, MJ, Zacharia, E, Karagiannides, I, Kyriazis, ID, Ntziachristos, P, Scerbo, DA, Brown, BR, Aifantis, I, Shulman, GI, Goldberg, IJ & Drosatos, K 2019, 'Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1865, no. 9, pp. 2125-2137. https://doi.org/10.1016/j.bbadis.2019.04.010

TY - JOUR

T1 - Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

AU - Pol, Christine J.

AU - Pollak, Nina M.

AU - Jurczak, Michael J.

AU - Zacharia, Effimia

AU - Karagiannides, Iordanes

AU - Kyriazis, Ioannis D.

AU - Ntziachristos, Panagiotis

AU - Scerbo, Diego A.

AU - Brown, Brett R.

AU - Aifantis, Iannis

AU - Shulman, Gerald I.

AU - Goldberg, I. J.

AU - Drosatos, Konstantinos

N1 - Funding Information: This work was supported by NHLBI “Pathway to Independence” K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur Förderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute ( R00CA188293-02 ), the American Society of Hematology , the Leukemia Research Foundation , the St. Baldrick's Foundation , and the Zell Foundation (P.N.), the “Stavros Niarchos Foundation”-RTP-CEM fellowship by the World Hellenic Biomedical Association -WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation , the Leukemia & Lymphoma Society , the Ralph S. French Charitable Foundation Trust , the Chemotherapy Foundation , the V Foundation for Cancer Research , the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. Funding Information: We would like to thank Mesele C. Valenti for technical assistance. The graphical abstract was produced using Servier Medical Art (http://www.servier.com). Conceptualization K.D. C.J.P.; Methodology, K.D. C.J.P. N.M.P. M.J.J. E.Z. I.D.K. P.N.; Validation, C.J.P. N.M.P.; Formal Analysis, C.J.P. N.M.P. M.J.J. E.Z. I.D.K. I.K.; Investigation, C.J.P, N.M.P. M.J.J. E.Z. I.K. I.D.K. D.A.S, B.R.B. and K.D.; Resources, K.D. I.J.G. G.I.S. I.A.; Writing ? Original Draft, C.J.P. K.D.; Writing ? Review & Editing, C.J.P. N.M.P. M.J.J. E.Z. I.K. I.D.K. P.N. I.A. G.I.S. I.J.G. K.D.; Supervision K.D.; Project administration, C.J.P. K.D.; Funding Acquisition, K.D, I.J.G. I.A. P.N. This work was supported by NHLBI ?Pathway to Independence? K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur F?rderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, and the Zell Foundation (P.N.), the ?Stavros Niarchos Foundation?-RTP-CEM fellowship by the World Hellenic Biomedical Association-WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. Funding Information: We would like to thank Mesele C. Valenti for technical assistance. The graphical abstract was produced using Servier Medical Art (http://www.servier.com). Conceptualization K.D. C.J.P.; Methodology, K.D. C.J.P. N.M.P. M.J.J. E.Z. I.D.K. P.N.; Validation, C.J.P. N.M.P.; Formal Analysis, C.J.P. N.M.P. M.J.J. E.Z. I.D.K. I.K.; Investigation, C.J.P, N.M.P. M.J.J. E.Z. I.K. I.D.K. D.A.S, B.R.B. and K.D.; Resources, K.D. I.J.G. G.I.S. I.A.; Writing – Original Draft, C.J.P. K.D.; Writing – Review & Editing, C.J.P. N.M.P. M.J.J. E.Z. I.K. I.D.K. P.N. I.A. G.I.S. I.J.G. K.D.; Supervision K.D.; Project administration, C.J.P. K.D.; Funding Acquisition, K.D, I.J.G. I.A. P.N. This work was supported by NHLBI “Pathway to Independence” K99/R00 award HL112853 (K.D.), HL130218 (K.D.), HL45095 and HL73029 (I.J.G.), the W. W. Smith Charitable Trust (K.D.), the FWF project DK-MCD W1226 of the Austrian Science Fund [Fonds zur Förderung der wissenschaftlichen Forschung (FWF)] (N.M.P.), the National Cancer Institute (R00CA188293-02), the American Society of Hematology, the Leukemia Research Foundation, the St. Baldrick's Foundation, and the Zell Foundation (P.N.), the “Stavros Niarchos Foundation”-RTP-CEM fellowship by the World Hellenic Biomedical Association-WHBA (E.Z.), the American Heart Association and the Kahn Family Post-Doctoral Fellowship in Cardiovascular Research 18POST34060150 (I.D.K.), the William Lawrence and Blanche Hughes Foundation, the Leukemia & Lymphoma Society, the Ralph S. French Charitable Foundation Trust, the Chemotherapy Foundation, the V Foundation for Cancer Research, the St. Baldrick's Foundation (I.A.). I.A. is a Howard Hughes Medical Institute Early Career Scientist. Publisher Copyright: © 2019 Elsevier B.V.

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - FGF21

KW - Heart

KW - High fat diet

KW - Krüppel-like factor

KW - Obesity

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UR - http://www.scopus.com/inward/citedby.url?scp=85065030772&partnerID=8YFLogxK

U2 - 10.1016/j.bbadis.2019.04.010

DO - 10.1016/j.bbadis.2019.04.010

M3 - Article

C2 - 31029826

AN - SCOPUS:85065030772

SN - 0925-4439

VL - 1865

SP - 2125

EP - 2137

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

IS - 9

ER -

Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21

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