Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice
Objectives: Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are require...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001582 |
| _version_ | 1828107456125861888 |
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| author | Satish Patel Afreen Haider Anna Alvarez-Guaita Guillaume Bidault Julia Sarah El-Sayed Moustafa Esther Guiu-Jurado John A. Tadross James Warner James Harrison Samuel Virtue Fabio Scurria Ilona Zvetkova Matthias Blüher Kerrin S. Small Stephen O’Rahilly David B. Savage |
| author_facet | Satish Patel Afreen Haider Anna Alvarez-Guaita Guillaume Bidault Julia Sarah El-Sayed Moustafa Esther Guiu-Jurado John A. Tadross James Warner James Harrison Samuel Virtue Fabio Scurria Ilona Zvetkova Matthias Blüher Kerrin S. Small Stephen O’Rahilly David B. Savage |
| author_sort | Satish Patel |
| collection | DOAJ |
| description | Objectives: Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. Methods: Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice. Results: Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice. Conclusions: Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress. |
| first_indexed | 2024-04-11T10:31:22Z |
| format | Article |
| id | doaj.art-86d575de029d49f1be5d61f2c525a70f |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-11T10:31:22Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-86d575de029d49f1be5d61f2c525a70f2022-12-22T04:29:24ZengElsevierMolecular Metabolism2212-87782022-11-0165101589Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed miceSatish Patel0Afreen Haider1Anna Alvarez-Guaita2Guillaume Bidault3Julia Sarah El-Sayed Moustafa4Esther Guiu-Jurado5John A. Tadross6James Warner7James Harrison8Samuel Virtue9Fabio Scurria10Ilona Zvetkova11Matthias Blüher12Kerrin S. Small13Stephen O’Rahilly14David B. Savage15University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Corresponding author.University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Corresponding author.University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UKDepartment of Twin Research and Genetic Epidemiology, King’s College London, St Thomas’ Campus, London, SE1 7EH, UKMedical Department III – Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, GermanyUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; East Midlands and East of England Genomic Laboratory Hub & Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UKDepartment of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UKMedical Department III – Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, GermanyDepartment of Twin Research and Genetic Epidemiology, King’s College London, St Thomas’ Campus, London, SE1 7EH, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UKUniversity of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Cambridge, CB2 0QQ, UK; MRC Metabolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; Corresponding author.Objectives: Obesity in humans and mice is associated with elevated levels of two hormones responsive to cellular stress, namely GDF15 and FGF21. Over-expression of each of these is associated with weight loss and beneficial metabolic changes but where they are secreted from and what they are required for physiologically in the context of overfeeding remains unclear. Methods: Here we used tissue selective knockout mouse models and human transcriptomics to determine the source of circulating GDF15 in obesity. We then generated and characterized the metabolic phenotypes of GDF15/FGF21 double knockout mice. Results: Circulating GDF15 and FGF21 are both largely derived from the liver, rather than adipose tissue or skeletal muscle, in obese states. Combined whole body deletion of FGF21 and GDF15 does not result in any additional weight gain in response to high fat feeding but it does result in significantly greater hepatic steatosis and insulin resistance than that seen in GDF15 single knockout mice. Conclusions: Collectively the data suggest that overfeeding activates a stress response in the liver which is the major source of systemic rises in GDF15 and FGF21. These hormones then activate pathways which reduce this metabolic stress.http://www.sciencedirect.com/science/article/pii/S2212877822001582GDF15FGF21Insulin resistanceObesity |
| spellingShingle | Satish Patel Afreen Haider Anna Alvarez-Guaita Guillaume Bidault Julia Sarah El-Sayed Moustafa Esther Guiu-Jurado John A. Tadross James Warner James Harrison Samuel Virtue Fabio Scurria Ilona Zvetkova Matthias Blüher Kerrin S. Small Stephen O’Rahilly David B. Savage Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice Molecular Metabolism GDF15 FGF21 Insulin resistance Obesity |
| title | Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice |
| title_full | Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice |
| title_fullStr | Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice |
| title_full_unstemmed | Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice |
| title_short | Combined genetic deletion of GDF15 and FGF21 has modest effects on body weight, hepatic steatosis and insulin resistance in high fat fed mice |
| title_sort | combined genetic deletion of gdf15 and fgf21 has modest effects on body weight hepatic steatosis and insulin resistance in high fat fed mice |
| topic | GDF15 FGF21 Insulin resistance Obesity |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001582 |
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