Transmembrane G protein-coupled receptor 5 signaling stimulates fibroblast growth factor 21 expression concomitant with up-regulation of the transcription factor nuclear receptor Nr4a1

Fibroblast growth factor 21 (FGF21) acts as an endocrine factor, playing important roles in the regulation of energy homeostasis, glucose and lipid metabolism. It is induced by diverse metabolic and cellular stresses, such as starvation and cold challenge, which in turn facilitate adaptation to the...

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Published in:	Biomedicine & pharmacotherapy Vol. 142; p. 112078
Main Authors:	Kiyama, Genki, Nakashima, Ken-ichi, Shimada, Kazumasa, Murono, Naoko, Kakihana, Wataru, Imai, Hideki, Inoue, Makoto, Hirai, Takao
Format:	Journal Article
Language:	English
Published:	France Elsevier Masson SAS 01-10-2021 Elsevier
Subjects:	3-O-acetyloleanolic acid Animals Anti-Obesity Agents - isolation & purification Anti-Obesity Agents - pharmacology Cell Line FGF21 Fibroblast Growth Factors - genetics Forsythia - chemistry Male Mice Muscle Fibers, Skeletal - cytology Muscle Fibers, Skeletal - drug effects Myoblasts - cytology Myoblasts - drug effects Nr4a1 Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics p38 p38 Mitogen-Activated Protein Kinases - metabolism Receptors, G-Protein-Coupled - drug effects Receptors, G-Protein-Coupled - metabolism TGR5 Triterpenes - isolation & purification Triterpenes - pharmacology Up-Regulation FXR TGR5 Oleanolic acid (PubChem CID: 10494) NAFLD p38 3-O-acetyloleanolic acid (PubChem CID: 151202) 3-O-acetyloleanolic acid SB203580 (PubChem CID: 176155) FGF21 Nr4a1
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Summary:	Fibroblast growth factor 21 (FGF21) acts as an endocrine factor, playing important roles in the regulation of energy homeostasis, glucose and lipid metabolism. It is induced by diverse metabolic and cellular stresses, such as starvation and cold challenge, which in turn facilitate adaptation to the stress environment. The pharmacological action of FGF21 has received much attention, because the administration of FGF21 or its analogs has been shown to have an anti-obesity effect in rodent models. In the present study, we found that 3-O-acetyloleanolic acid, an active constituent isolated from the fruits of Forsythia suspensa, stimulated FGF21 production concomitant with the up-regulation of a transcription factor, nuclear receptor Nr4a1, in C2C12 myotubes. Additionally, significant increases in mFgf21 promoter activity were observed in C2C12 cells overexpressing TGR5 receptor in response to 3-O-acetyloleanolic acid treatment. Treatment with the p38 MAPK inhibitor SB203580 was effective at suppressing these stimulatory effects of 3-O-acetyloleanolic acid. Pretreatment with SB203580 also significantly repressed FGF21 mRNA abundance and FGF21 secretion in C2C12 myotubes after 3-O-acetyloleanolic acid stimulation, suggesting that p38 activation is required for the induction of FGF21 by ligand-activated TGR5 in C2C12 myotubes. These findings collectively indicated that TGR5 receptor signaling drives FGF21 expression via p38 activation, at least partly, by mediating Nr4a1 expression. Thus, the novel biological function of 3-O-acetyloleanolic acid as an agent having anti-obesity effects is likely to be mediated through the activation of TGR5 receptors. [Display omitted] •3-O-acetyloleanolic acid, an active constituent isolated from the fruits of Forsythia suspensa, stimulated FGF21 in C2C12 myotubes.•TGR5 receptor signaling drives FGF21 expression via p38 activation.•Up-regulation of Nr4a1 after stimulation with 3-O-acetyloleanolic acid regulates FGF21.•Biological function of 3-O-acetyloleanolic acid as an agent having anti-obesity effects is likely mediated through the activation of TGR5.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0753-3322 1950-6007
DOI:	10.1016/j.biopha.2021.112078