Fibroblast growth factor 21 is induced upon cardiac stress and alters cardiac lipid homeostasis

Fibroblast growth factor 21 (FGF21) is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPARα-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism. Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis. Fibroblast growth factor 21 (FGF21) is a PPARα-regulated gene elucidated in the liver of PPARα-deficient mice or PPARα agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPARα-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Here we show that FGF21 mRNA expression is markedly increased in the heart of ATGL-deficient mice accompanied by elevated expression of endoplasmic reticulum (ER) stress markers, which can be reversed by reconstitution of ATGL expression in cardiac muscle. In line with this assumption, the induction of ER stress increases FGF21 mRNA expression in H9C2 cardiomyotubes. Cardiac FGF21 expression was also induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. To address this question, we generated and characterized mice with cardiac-specific overexpression of FGF21 (CM-Fgf21). FGF21 was efficiently secreted from cardiomyocytes of CM-Fgf21 mice, which moderately affected cardiac TG homeostasis, indicating a role for FGF21 in cardiac energy metabolism. Together, our results show that FGF21 expression is activated upon cardiac ER stress linked to defective lipolysis and that a persistent increase in circulating FGF21 levels interferes with cardiac and whole body energy homeostasis. Fibroblast growth factor 21 (FGF21) is an important regulator in energy metabolism, and the hormone-like properties of FGF21 are implicated in the adaptation to energy restriction and fasting (1Badman M.K. Pissios P. Kennedy A.R. Koukos G. Flier J.S. Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.Cell Metab. 2007; 5: 426-437Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar, 2Gälman C. Lundåsen T. Kharitonenkov A. Bina H.A. Eriksson M. Hafström I. Dahlin M. Amark P. Angelin B. Rudling M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man.Cell Metab. 2008; 8: 169-174Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar, 3Inagaki T. Dutchak P. Zhao G. Ding X. Gautron L. Parameswara V. Li Y. Goetz R. Mohammadi M. Esser V. et al.Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21.Cell Metab. 2007; 5: 415-425Abstract Full Text Full Text PDF PubMed Scopus (1191) Google Scholar). FGF21 is most abundantly expressed in the liver of fasted mice and is released into the circulation, where the protein shows pleiotropic effects on target tissues including adipose tissue, pancreatic islets, and the liver itself (4Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1626) Google Scholar, 5Kharitonenkov A. Larsen P. FGF21 reloaded: challenges of a rapidly growing field.Trends Endocrinol. Metab. 2011; 22: 81-86Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 6Potthoff M.J. Kliewer S.A. Mangelsdorf D.J. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine.Genes Dev. 2012; 26: 312-324Crossref PubMed Scopus (346) Google Scholar). The action of FGF21 in the periphery and in the liver is mediated via binding to FGF receptors in a β-Klotho-dependent manner (7Kharitonenkov A. Dunbar J.D. Bina H.A. Bright S. Moyers J.S. Zhang C. Ding L. Micanovic R. Mehrbod S.F. Knierman et and activation is by 2008; PubMed Scopus Google Scholar, Y. M. A. Goetz R. Mohammadi M. M. is for metabolic of fibroblast growth factor 2007; PubMed Scopus Google Scholar, M. Y. Y. M. M. A. S. T. is for fibroblast growth factor 21 FGF and Endocrinol. 2008; 22: PubMed Scopus Google Scholar). FGF21 mRNA expression is by a that the expression of implicated in and P. G. B. the of PPARα in energy metabolism and Clin. Invest. PubMed Scopus Google Scholar). the catabolism of and the of are important energy and that are for can from from adipose TG or from TG catabolism of TG R. R. G. A. and lipolysis in lipid metabolism and Metab. 2012; Full Text Full Text PDF PubMed Scopus Google Scholar). In most the and in TG catabolism is by adipose triglyceride lipase which G. A. R. G. C. G. R. C. S. et lipolysis and energy metabolism in mice lacking adipose triglyceride PubMed Scopus Google Scholar, R. G. G. R. M. A. G. A. R. in adipose is by adipose triglyceride PubMed Scopus Google Scholar). TG catabolism on the of the ATGL protein gene A. R. G. M. G. M. P. G. R. triglyceride lipolysis of is activated by and defective in Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). Mice lacking in exhibit cardiac linked to impaired gene expression S. G. A. M. et cardiac lipolysis in mice on gene Full Text Full Text PDF PubMed Scopus Google Scholar). we and that TG catabolism is to gene expression and to the induction of G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar, triglyceride lipase is a hepatic lipase that and and 2011; PubMed Scopus Google Scholar, Hepatic Full Text Full Text PDF PubMed Scopus Google Scholar). The of PPARα-activated gene and is most in mice lacking defective TG catabolism in ATGL-deficient mice cardiac and increased hepatic TG levels to a defect in PPARα-activated gene expression and in the heart and liver, G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar, triglyceride lipase is a hepatic lipase that and and 2011; PubMed Scopus Google Scholar). In with this hepatic FGF21 mRNA expression levels are in ATGL-deficient mice, to a marked in circulating FGF21 protein levels P. T. A. M. E. A. R. R. G. M. of adipose triglyceride lipase in from hepatic in of and Scopus Google Scholar). Here we show that FGF21 mRNA expression is increased in cardiac of mice globally lacking ATGL or lacking the ATGL gene in mRNA expression of PPARα-regulated and cardiac FGF21 mRNA expression was by cardiac ER stress in of ATGL-deficient mice. The induction of FGF21 expression in H9C2 to ER stress that FGF21 expression is by cardiac ER the induction of FGF21 mRNA expression in of fasted mice with in cardiac TG of mice with cardiac-specific FGF21 overexpression a role of FGF21 in cardiac energy metabolism. Mice globally lacking ATGL generated as G. A. R. G. C. G. R. C. S. et lipolysis and energy metabolism in mice lacking adipose triglyceride PubMed Scopus Google Scholar). Mice ATGL in generated by the ATGL an ATGL-deficient G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). Mice with and mice in the heart generated as S. G. A. M. et cardiac lipolysis in mice on gene Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. R. S. P. C. et overexpression of cardiac via the of a Full Text Full Text PDF PubMed Scopus Google Scholar). The PPARα was via a for mice the of the generated by from a liver the and including a restriction the which are and for in the A. S. of the in the gene Full Text PDF PubMed Google by mice from a and for on for and mice with cardiac-specific overexpression with to the in a and on a with to a and mice by and tissues The and from mice was by the for and and by the of the of by from mice. by from and and levels the levels of FGF21 and from and was with the and with of was for and of of and of and mRNA levels the with as are in in the heart H9C2 from and in and H9C2 by the of to including the of FGF21 from or was into and of was to a B. S. T. A.M. L. gene of protein in mice and Full Text PDF PubMed Google Scholar). H9C2 into a of for H9C2 with for or FGF21 a of of or was H9C2 in and with FGF21 or with with and with with and The of into the TG was of or of for with and with of lipid by as to TG and in and was by with of and for protein the to the of M. for the and of from Full Text PDF PubMed Google Scholar). in a of and by in TG of H9C2 and with was as the was by of and for of and or was and for The was by with of and the was by the and with with of and for of protein of was and by a of in as and for by in with of for was to a and into the of the The was by the of the the and The was and with was for and the was to a for the in the was and with of for of protein the Mice fasted for and with of body levels and and an was of the can be in the in H9C2 with or FGF21 was by with with with for with and of was for of was for protein and for in was to the of et T. E. E. B. C. S. et by PubMed Scopus Google and is in in the TG as A. R. G. M. G. M. P. G. R. triglyceride lipolysis of is activated by and defective in Metab. Full Text Full Text PDF PubMed Scopus Google Scholar). of the of and can be in the H9C2 with with of for with and was of In for in with or was as for with with and was as Cardiac of mice was in and on an The was for and the and for by by and for protein a FGF21 for and or a of and in a and by of FGF21 released from FGF21 of was to of and on for was for The was and of was to and for to from the in of and a protein and by a Mice in a that the of and of the body for the of Mice to for and B. L. M. et of by in Clin. Invest. PubMed Scopus Google of the can be in the in H9C2 H9C2 in growth and was was to The was was was upon of are as was by the for and Mice globally lacking ATGL show a marked defect in PPARα-activated gene expression in and liver G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). In with the role of FGF21 as a PPARα-regulated gene (1Badman M.K. Pissios P. Kennedy A.R. Koukos G. Flier J.S. Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.Cell Metab. 2007; 5: 426-437Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar, 3Inagaki T. Dutchak P. Zhao G. Ding X. Gautron L. Parameswara V. Li Y. Goetz R. Mohammadi M. Esser V. et al.Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21.Cell Metab. 2007; 5: 415-425Abstract Full Text Full Text PDF PubMed Scopus (1191) Google and P. T. A. M. E. A. R. R. G. M. of adipose triglyceride lipase in from hepatic in of and Scopus Google a reduction in FGF21 mRNA expression in the liver of mice accompanied by a in circulating FGF21 Here we show that FGF21 mRNA expression is increased in of mice impaired expression of PPARα-regulated G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). The induction of FGF21 expression in of mice be an adaptation to the reduction in hepatic FGF21 mRNA expression and to the circulating FGF21 levels P. T. A. M. E. A. R. R. G. M. of adipose triglyceride lipase in from hepatic in of and Scopus Google Scholar). To address this we FGF21 mRNA expression in mice ATGL in on an ATGL-deficient The of ATGL expression in markedly FGF21 mRNA levels in cardiac of fasted mice indicating that the increase in FGF21 mRNA expression of mice from the of ATGL in In with this assumption, we a marked increase in FGF21 mRNA expression levels in of mice lacking the ATGL in mRNA levels of from to to we in of mice G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). FGF21 mRNA expression levels in mice with upon of the PPARα mRNA levels of PPARα to levels that cardiac-specific overexpression cardiac TG which was with heart M. M. R. S. P. C. et overexpression of cardiac via the of a Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. Y. et overexpression to and cardiac Full Text Full Text PDF PubMed Scopus Google Scholar). FGF21 mRNA levels also increased in of mice with mice. In to the induction of FGF21 expression in of mice, mRNA expression of the FGF21 which is for FGF21 (7Kharitonenkov A. Dunbar J.D. Bina H.A. Bright S. Moyers J.S. Zhang C. Ding L. Micanovic R. Mehrbod S.F. Knierman et and activation is by 2008; PubMed Scopus Google Scholar, Y. M. A. Goetz R. Mohammadi M. M. is for metabolic of fibroblast growth factor 2007; PubMed Scopus Google Scholar, M. Y. Y. M. M. A. S. T. is for fibroblast growth factor 21 FGF and Endocrinol. 2008; 22: PubMed Scopus Google was in of and mice with hepatic mRNA expression levels of mice In to cardiac mRNA protein expression in the levels in and mice with ER stress linked to cardiac including and cardiac and heart heart M. with endoplasmic reticulum stress in the PubMed Scopus Google Scholar, T. M. ER stress in Full Text Full Text PDF PubMed Scopus Google Scholar). The marked defect in cardiac energy metabolism of mice to protein expression levels of implicated in ER expression of the ER stress protein and protein increased in of mice In protein levels of and The reconstitution of ATGL expression in of mice protein levels to that ER stress mRNA expression in of mice. we fasting mRNA expression levels of from the ER stress mRNA expression of from the ER stress or in mice with mice, indicating that fasting an ER response that ER stress FGF21 mRNA expression in and Fibroblast growth factor 21 is induced by endoplasmic reticulum PubMed Scopus Google and is that ER stress be a for FGF21 expression in of mice that mice are from hepatic ER T. P. G. M.J. T. E. et of adipose triglyceride lipase from hepatic endoplasmic reticulum stress in 2012; PubMed Scopus Google Scholar). To address this we H9C2 with for to ER stress and mRNA levels of stress and markedly induced FGF21 mRNA levels and increased mRNA expression of for the induction of stress including a stress and increased mRNA levels of and which are for induction of the protein response reticulum stress in liver 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). To ER stress is a of FGF21 expression in we H9C2 with or for which are of ER stress Y. M.J. endoplasmic reticulum stress and of in liver Endocrinol. Metab. PubMed Scopus Google Scholar, M. L. in the endoplasmic reticulum cardiomyocytes from Clin. Google Scholar). with or markedly FGF21 mRNA accompanied by increased mRNA levels of implicated in the ER stress from to Together, that ER stress is an of FGF21 expression in by our that FGF21 expression is induced in the we FGF21 expression in the heart is also regulated by the energy Cardiac FGF21 mRNA expression levels are increased in fasted mice and levels upon prolonged fasting for In the fasted the heart on TG as energy FGF21 expression a role of FGF21 in cardiac TG metabolism. we the of FGF21 overexpression on TG in H9C2 H9C2 to and with FGF21 or or FGF21 protein was in with as as in the that FGF21 is also secreted from H9C2 with as and and by FGF21 expression increased the of into the TG of H9C2 and and with with The increase in into TG was from to The increased of into TG of H9C2 upon with the FGF21 can be the of elevated impaired or of released TG To address this question, we of H9C2 upon with by the of in was in with that the TG in was markedly with that the increased TG in H9C2 is a of TG generated by TG catabolism can be into the TG in a which TG homeostasis. To the of FGF21 expression on and TG homeostasis, H9C2 with and with the the was by the to of that the of into the TG was increased to a in with the of the of with indicating that was affected by FGF21 TG catabolism in H9C2 FGF21 a metabolic to To FGF21 overexpression in H9C2 H9C2 with FGF21 and and with or the of with FGF21 increased with The with increased in and H9C2 cardiac to a and indicating that FGF21 expression in an an elevated of with with which is of increased in response to FGF21 overexpression The defect of from ATGL-deficient mice to FGF21 overexpression interferes with in H9C2 cardiomyotubes. and in H9C2 with FGF21 and in and FGF21 and Together, that FGF21 overexpression interferes with and To our in that FGF21 expression energy metabolism in H9C2 we generated mice with cardiac-specific of FGF21 (CM-Fgf21). was generated by the of the and of the into the of increased in from CM-Fgf21 mice, FGF21 protein in cardiac of FGF21 levels markedly increased in CM-Fgf21 mice with mice, that FGF21 is efficiently secreted from the heart of mice. that mice with FGF21 overexpression markedly increased FGF21 levels accompanied by growth (4Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1626) Google Scholar, T. Goetz R. Mohammadi M. Mangelsdorf D.J. Kliewer S.A. of growth by the Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). In our cardiac FGF21 FGF21 levels also associated with body to a CM-Fgf21 mice a increase in body which was by a reduction in body we of and mice, including body and which to be affected by increased circulating FGF21 levels (4Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1626) Google Scholar, T. Goetz R. Mohammadi M. Mangelsdorf D.J. Kliewer S.A. of growth by the Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google Scholar). levels in and fasted CM-Fgf21 mice and with In levels of and increased by and in fasted CM-Fgf21 mice with levels in of CM-Fgf21 mice, with levels of mice with hepatic FGF21 in and fasted CM-Fgf21 and with a and an in from and fasted to mice are growth factor mice. in a with a and an in from and fasted to mice are growth factor mice. mice. to the increase of TG levels upon FGF21 overexpression in H9C2 cardiac-specific FGF21 overexpression a increase in cardiac TG levels of CM-Fgf21 mice we overexpression of FGF21 mRNA levels of from the ER stress mRNA expression of the ER stress and in CM-Fgf21 with The increase in TG levels of CM-Fgf21 be by in TG catabolism upon cardiac FGF21 To address this we TG in from fasted mice are as energy In with our results from H9C2 in of CM-Fgf21 with The cardiac of ATGL-deficient mice was to be a of impaired PPARα-activated expression of for G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). to mRNA levels of PPARα target in of fasted mice In to ATGL-deficient mice, cardiac-specific FGF21 overexpression moderately mRNA expression of PPARα-regulated including mRNA levels of and as by from cardiac upon with was in of CM-Fgf21 mice was elevated in liver from mice with cardiac in CM-Fgf21 mice that cardiac overexpression of FGF21 with cardiac cardiac heart in CM-Fgf21 mice we the in cardiac TG of CM-Fgf21 mice cardiac To we with as and the of as a of and was increased in of CM-Fgf21 with and adipose a increased of protein was in of CM-Fgf21 mice with implicating in cardiac from the of CM-Fgf21 mice was implicating in mice with cardiac-specific FGF21 we and for as a for whole body energy metabolism. was increased in the of CM-Fgf21 mice was to in the is of be mice as energy The increase in the of CM-Fgf21 mice is an of a increased whole body which be a of the increase in FGF21 levels of mice. that the heart is to FGF21 into the circulation, to increased FGF21 which in cardiac and whole body energy metabolism. a was as a FGF21 target of the or expression of which is a for FGF21 S. T. M. et and action of FGF21 in with liver and adipose Endocrinol. Metab. PubMed Scopus Google Scholar, Bina H.A. Flier J.S. Kharitonenkov A. Maratos-Flier E. regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in 2011; PubMed Scopus Google Scholar, Li Bina H.A. Kharitonenkov A. Fibroblast growth factor 21 via regulation of hepatic and PubMed Scopus Google Scholar). this was by the of et and et V. R. M. into the effects of FGF21 in and PubMed Scopus Google that and FGF21 are expressed in cardiomyocytes and that mice globally lacking FGF21 exhibit increased heart and a cardiac Here we show that FGF21 mRNA expression is increased in the heart of mice. shows that FGF21 mRNA expression is in the liver of mice, which was by markedly circulating FGF21 levels P. T. A. M. E. A. R. R. G. M. of adipose triglyceride lipase in from hepatic in of and Scopus Google Scholar). The role of FGF21 as PPARα-regulated gene in the liver (1Badman M.K. Pissios P. Kennedy A.R. Koukos G. Flier J.S. Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states.Cell Metab. 2007; 5: 426-437Abstract Full Text Full Text PDF PubMed Scopus (1171) Google Scholar, 3Inagaki T. Dutchak P. Zhao G. Ding X. Gautron L. Parameswara V. Li Y. Goetz R. Mohammadi M. Esser V. et al.Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21.Cell Metab. 2007; 5: 415-425Abstract Full Text Full Text PDF PubMed Scopus (1191) Google with the marked defect in gene expression in the liver of mice G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google or in mice with hepatic ATGL triglyceride lipase is a hepatic lipase that and and 2011; PubMed Scopus Google that the in hepatic FGF21 mRNA of is a PPARα gene expression is impaired in of mice that the increase in cardiac FGF21 expression is a The marked reduction in cardiac FGF21 mRNA expression of mice an ATGL in that the induction of cardiac FGF21 expression from in cardiac metabolism and from an adaptation to in energy of mice. associated with cardiac ER stress M. with endoplasmic reticulum stress in the PubMed Scopus Google Scholar). The increase in FGF21 mRNA expression in of mice was associated with increased protein expression of from the ER stress and to ATGL expression was in the that ER stress is a for cardiac FGF21 expression. is by the induction of FGF21 expression in H9C2 with ER including and Mice lacking the ATGL in S. G. A. M. et cardiac lipolysis in mice on gene Full Text Full Text PDF PubMed Scopus Google show a increase in cardiac FGF21 expression. FGF21 mRNA levels upon PPARα which to cardiac and to cardiac in ATGL-deficient mice G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). is that impaired ER stress in of mice, which FGF21 expression. In line with this assumption, the by et S.A. C. P. A. S. S. R. A. of stress of in the Metab. Full Text Full Text PDF PubMed Scopus Google shows that an increase in the protein response in the heart elevated mRNA expression as in linked to with elevated FGF21 expression. the increase in cardiac FGF21 expression of mice by impaired that the in FGF21 expression with the of and ER the role of FGF21 in the of that is an in mice Y. Bina H.A. Y. Kharitonenkov A. FGF21 is an 2008; PubMed Scopus Google and P. M. A.R. R. C. T. S. Fibroblast growth is induced in by PubMed Scopus Google and that to an induction of FGF21 mRNA expression in S. T. A. V. et a PubMed Scopus Google Scholar). is that increased FGF21 expression in of the and in C. C. FGF21 and expression are of in PubMed Scopus Google is for increased circulating FGF21 are in with a in where a and increased FGF21 levels was A. M. P. T. S. et al.FGF-21 as a for a 2011; Full Text Full Text PDF PubMed Scopus Google Scholar). The FGF21 levels in mice FGF21 levels as a for hepatic in mice. In this we also show that cardiac FGF21 mRNA expression increases in fasted mice indicating a role of FGF21 in cardiac energy metabolism FGF21 overexpression and increased TG in H9C2 cardiac which was by TG and increased and was moderately that FGF21 expression the is The role of FGF21 in (4Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1626) Google Scholar, I. M. Fibroblast growth factor 21: a novel metabolic regulator with properties in PubMed Google can be to and is linked to TG as energy To the role of FGF21 in cardiac energy metabolism, we generated a with cardiac-specific overexpression of FGF21 was efficiently expressed and secreted from the heart of mice, to a with mice with FGF21 overexpression (4Kharitonenkov A. Shiyanova T.L. Koester A. Ford A.M. Micanovic R. Galbreath E.J. Sandusky G.E. Hammond L.J. Moyers J.S. Owens R.A. et al.FGF-21 as a novel metabolic regulator.J. Clin. Invest. 2005; 115: 1627-1635Crossref PubMed Scopus (1626) Google Scholar, T. Goetz R. Mohammadi M. Mangelsdorf D.J. Kliewer S.A. of growth by the Metab. 2008; 8: Full Text Full Text PDF PubMed Scopus Google increased FGF21 body and body increased body and and with in TG upon FGF21 overexpression in H9C2 we increased TG in of mice with cardiac-specific FGF21 which was by cardiac TG and a reduction in the expression of PPARα target in was moderately which be a of impaired as for mice lacking ATGL or in S. G. A. M. et cardiac lipolysis in mice on gene Full Text Full Text PDF PubMed Scopus Google Scholar, G. T. G. S. A. T. M. et catabolism cardiac via and 2011; PubMed Scopus Google Scholar). The that CM-Fgf21 mice exhibit heart that in is moderately affected as with the marked defect in and cardiac of ATGL-deficient mice. CM-Fgf21 mice in cardiac impaired TG is that cardiac in CM-Fgf21 is increased in our the increase in body levels of CM-Fgf21 mice cardiac body the of TG that FGF21 cardiac and heart in response to A. I. E. M. C. R. M. M. M. et growth factor 21 cardiac in PubMed Scopus Google Scholar, Kharitonenkov A. Zhang B. Li Zhang Endocrine of by FGF21 from the liver and adipose PubMed Scopus Google which that the heart is a that be expressed in levels in and FGF21 via binding to in with fibroblast growth factor In line with we protein expression in of and mice, indicating that FGF21 cardiac energy metabolism in an this and that FGF21 cardiac in from V. R. M. into the effects of FGF21 in and PubMed Scopus Google which be also mediated via results from our mice that cardiac FGF21 a role in cardiac energy metabolism healthy an important role in the heart or as a for cardiac cardiac ER The Kliewer for the FGF21 and B. B. and A. for in and with adipose triglyceride lipase gene cardiac endoplasmic reticulum fibroblast growth factor 21 of