Abstract
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.
Highlights
Fibroblast growth factor 21 (FGF21) is a PPAR␣regulated gene elucidated in the liver of PPAR␣-deficient mice or PPAR␣ agonist-treated mice
In accordance with this assumption, we found a marked 9.3-fold increase in FGF21 mRNA expression levels in cardiac muscle (CM) of mice lacking the adipose triglyceride lipase (ATGL) coactivator comparative gene identification-58 (CGI-58) exclusively in muscle, whereas mRNA levels of established PPAR␣-target genes were decreased similar to what we reported in CM of ATGL-ko mice [16]
We show that FGF21 mRNA expression is strongly increased in the steatotic heart of ATGL-ko mice
Summary
Fibroblast growth factor 21 (FGF21) is a PPAR␣regulated gene elucidated in the liver of PPAR␣-deficient mice or PPAR␣ agonist-treated mice. Mice globally lacking adipose triglyceride lipase (ATGL) exhibit a marked defect in TG catabolism associated with impaired PPAR␣-activated gene expression in the heart and liver, including a drastic reduction in hepatic FGF21 mRNA expression. Cardiac FGF21 expression was induced upon fasting of healthy mice, implicating a role of FGF21 in cardiac energy metabolism. Supplementary key words adipose triglyceride lipase cardiac lipid and energy metabolism ER stress properties of FGF21 are implicated in the adaptation to energy restriction and fasting [1,2,3]. The interconnection of lipolysis, PPAR␣-activated gene expression, and mitochondrial FAO is most exemplified in mice lacking ATGL: Fibroblast growth factor 21 (FGF21) is an important regulator in energy metabolism, and the hormone-like.
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