title: Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.
abstract: Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function.
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Fuhrmeister
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Zota
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Tjeerd P
authors.initials: TP
authors.lastname: Sijmonsma
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Oksana
authors.initials: O
authors.lastname: Seibert
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Şahika
authors.initials: Ş
authors.lastname: Cıngır
authors.affiliation: Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schmidt
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Vallon
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Roldan M
authors.initials: RM
authors.lastname: de Guia
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Niopek
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Berriel Diaz
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany.
authors.forename: Adriano
authors.initials: A
authors.lastname: Maida
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Neuherberg, Germany stephan.herzig@helmholtz-muenchen.de a.rose@dkfz.de.
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.affiliation: Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University Hospital, Heidelberg, Germany stephan.herzig@helmholtz-muenchen.de a.rose@dkfz.de.
authors.forename: Adam J
authors.identifier: 0000-0001-9132-8244
authors.initials: AJ
authors.lastname: Rose
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005215:Fasting; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D009687:Nuclear Proteins; C493320:Fabp1 protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins
keywords: FABP1; hormesis; lipid; metabolism; stress