title: Lactate induces FGF21 expression in adipocytes through a p38-MAPK pathway.
abstract: FGF21 (fibroblast growth factor 21), first described as a main fasting-responsive molecule in the liver, has been shown to act as a true metabolic regulator in additional tissues, including muscle and adipose tissues. In the present study, we found that the expression and secretion of FGF21 was very rapidly increased following lactate exposure in adipocytes. Using different pharmacological and knockout mice models, we demonstrated that lactate regulates Fgf21 expression through a NADH/NAD-independent pathway, but requires active p38-MAPK (mitogen activated protein kinase) signalling. We also demonstrated that this effect is not restricted to lactate as additional metabolites including pyruvate and ketone bodies also activated the FGF21 stress response. FGF21 release by adipose cells in response to an excess of intermediate metabolites may represent a physiological mechanism by which the sensing of environmental metabolic conditions results in the release of FGF21 to improve metabolic adaptations.
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Jeanson
authors.affiliation: Departament de Bioquimica i Biologia Molecular, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av Diagonal 643, 08028 Barcelona, Spain CIBER Fisiopatologia de la Obesidad y Nutricion, Av Diagonal 643, 08028 Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Ribas
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France Laboratoire de Biochimie Nutritionnelle, IFB-Purpan, F- 31 059 Toulouse, Cedex 9, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Galinier
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Arnaud
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Ducos
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: André
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Chenouard
authors.affiliation: Departament de Bioquimica i Biologia Molecular, and Institute of Biomedicine (IBUB), Universitat de Barcelona, Av Diagonal 643, 08028 Barcelona, Spain CIBER Fisiopatologia de la Obesidad y Nutricion, Av Diagonal 643, 08028 Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Villarroya
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Casteilla
authors.affiliation: STROMALab, Université de Toulouse, CNRS, EFS, ENVT, INSERM, BP 84225, F-31 432 Toulouse Cedex 4, France audrey.carriere-pazat@inserm.fr.
authors.forename: Audrey
authors.initials: A
authors.lastname: Carrière
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007773:Lactates / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism; D000071256:Uncoupling Protein 1; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C081452:Atf4 protein, mouse; D007473:Ion Channels; D007773:Lactates; D024101:Mitochondrial Proteins; D047493:PPAR alpha; D047495:PPAR gamma; C525046:Sirt3 protein, mouse; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C414620:fibroblast growth factor 21; D051701:Activating Transcription Factor 4; D005346:Fibroblast Growth Factors; D048051:p38 Mitogen-Activated Protein Kinases; D056566:Sirtuin 3; D037761:Sirtuins
keywords: FGF21; UCP1; adipocytes; lactate; p38-MAPK