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....
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| Format: | Article |
| Language: | English |
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Springer Nature
2016-05-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201505801 |
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| author | Jessica Fuhrmeister Annika Zota Tjeerd P Sijmonsma Oksana Seibert Şahika Cıngır Kathrin Schmidt Nicola Vallon Roldan M de Guia Katharina Niopek Mauricio Berriel Diaz Adriano Maida Matthias Blüher Jürgen G Okun Stephan Herzig Adam J Rose |
| author_facet | Jessica Fuhrmeister Annika Zota Tjeerd P Sijmonsma Oksana Seibert Şahika Cıngır Kathrin Schmidt Nicola Vallon Roldan M de Guia Katharina Niopek Mauricio Berriel Diaz Adriano Maida Matthias Blüher Jürgen G Okun Stephan Herzig Adam J Rose |
| author_sort | Jessica Fuhrmeister |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-01d8e283e740411db13c507463c1aa34 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2016-05-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-01d8e283e740411db13c507463c1aa342025-08-20T03:43:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842016-05-018665466910.15252/emmm.201505801Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic healthJessica Fuhrmeister0Annika Zota1Tjeerd P Sijmonsma2Oksana Seibert3Şahika Cıngır4Kathrin Schmidt5Nicola Vallon6Roldan M de Guia7Katharina Niopek8Mauricio Berriel Diaz9Adriano Maida10Matthias Blüher11Jürgen G Okun12Stephan Herzig13Adam J Rose14Joint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalDivision of Inherited Metabolic Diseases, University Children's HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalDepartment of Medicine, University of LeipzigDivision of Inherited Metabolic Diseases, University Children's HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalJoint Research Division Molecular Metabolic Control, German Cancer Research Center, Center for Molecular Biology, Heidelberg University and Heidelberg University HospitalAbstract 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.https://doi.org/10.15252/emmm.201505801FABP1hormesislipidmetabolismstress |
| spellingShingle | Jessica Fuhrmeister Annika Zota Tjeerd P Sijmonsma Oksana Seibert Şahika Cıngır Kathrin Schmidt Nicola Vallon Roldan M de Guia Katharina Niopek Mauricio Berriel Diaz Adriano Maida Matthias Blüher Jürgen G Okun Stephan Herzig Adam J Rose Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health EMBO Molecular Medicine FABP1 hormesis lipid metabolism stress |
| title | Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health |
| title_full | Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health |
| title_fullStr | Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health |
| title_full_unstemmed | Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health |
| title_short | Fasting‐induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health |
| title_sort | fasting induced liver gadd45β restrains hepatic fatty acid uptake and improves metabolic health |
| topic | FABP1 hormesis lipid metabolism stress |
| url | https://doi.org/10.15252/emmm.201505801 |
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