GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.
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Authors
Alvarez-Guaita, Anna
Melvin, Audrey
Rimmington, Debra
Dattilo, Alessia
Miedzybrodzka, Emily L
Maurin, Anne-Catherine
Roberts, Geoffrey P
Meek, Claire L
Virtue, Samuel
Sparks, Lauren M
Parsons, Stephanie A
Redman, Leanne M
Bray, George A
Liou, Alice P
Woods, Rachel M
Parry, Sion A
Jeppesen, Per B
Kolnes, Anders J
Harding, Heather P
Gribble, Fiona M
Hulston, Carl J
Farooqi, I Sadaf
Fafournoux, Pierre
Smith, Steven R
Jensen, Jorgen
Breen, Danna
Wu, Zhidan
Zhang, Bei B
Coll, Anthony P
Savage, David B
Publication Date
2019-03-05Journal Title
Cell Metab
ISSN
1550-4131
Publisher
Elsevier BV
Volume
29
Issue
3
Pages
707-718.e8
Language
eng
Type
Article
This Version
AM
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Patel, S., Alvarez-Guaita, A., Melvin, A., Rimmington, D., Dattilo, A., Miedzybrodzka, E. L., Cimino, I., et al. (2019). GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.. Cell Metab, 29 (3), 707-718.e8. https://doi.org/10.1016/j.cmet.2018.12.016
Abstract
GDF15 is an established biomarker of cellular stress. The fact that it signals via a specific hindbrain receptor, GFRAL, and that mice lacking GDF15 manifest diet-induced obesity suggest that GDF15 may play a physiological role in energy balance. We performed experiments in humans, mice, and cells to determine if and how nutritional perturbations modify GDF15 expression. Circulating GDF15 levels manifest very modest changes in response to moderate caloric surpluses or deficits in mice or humans, differentiating it from classical intestinally derived satiety hormones and leptin. However, GDF15 levels do increase following sustained high-fat feeding or dietary amino acid imbalance in mice. We demonstrate that GDF15 expression is regulated by the integrated stress response and is induced in selected tissues in mice in these settings. Finally, we show that pharmacological GDF15 administration to mice can trigger conditioned taste aversion, suggesting that GDF15 may induce an aversive response to nutritional stress.
Keywords
Cell Line, Animals, Mice, Inbred C57BL, Humans, Mice, Energy Intake, Adult, Middle Aged, Growth Differentiation Factor 15, Young Adult, Diet, High-Fat
Sponsorship
This work and authors were funded by the NIHR Cambridge Biomedical Research Centre; NIHR Rare Disease Translational Research Collaboration; Medical Research Council [MC_UU_12012/2 and MRC_MC_UU_12012/3]; MRC Metabolic Diseases Unit [MRC_MC_UU_12012/5 and MRC_MC_UU_12012.1]; Wellcome Trust Strategic Award [100574/Z/12/Z and 100140]; Wellcome Trust [107064 , 095515/Z/11/Z , 098497/Z/12/Z, 106262/Z/14/Z and 106263/Z/14/Z]; British Heart Foundation [RG/12/13/29853]; Addenbrooke’s Charitable Trust / Evelyn Trust Cambridge Clinical Research Fellowship [16-69]
US Department of Agriculture: 2010-34323-21052; EFSD project grant and a Royal College of Surgeons Research Fellowship, Diabetes UK Harry Keen intermediate clinical fellowship (17/0005712). European Research Council, Bernard Wolfe Health Neuroscience Endowment, Experimental Medicine Training Initiative/AstraZeneca and Medimmune.
Funder references
National Institute for Health Research (NIHR) (unknown)
European Commission and European Federation of Pharmaceutical Industries and Associations (EFPIA) FP7 Innovative Medicines Initiative (IMI) (1153372)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
MRC (Unknown)
Medical Research Council (MC_UU_12012/5)
Wellcome Trust (106262/Z/14/Z)
Wellcome Trust (107064/Z/15/Z)
Wellcome Trust (200848/Z/16/Z)
Wellcome Trust (100574/Z/12/Z)
Wellcome Trust (207462/Z/17/Z)
British Heart Foundation (None)
Diabetes UK (17/0005712)
Wellcome Trust (084812/Z/08/Z)
Medical Research Council (G0900554)
Medical Research Council (MC_UU_12012/1)
Medical Research Council (MC_UU_12012/2)
Medical Research Council (MC_UU_12012/3)
Wellcome Trust (095515/Z/11/Z)
Wellcome Trust (098497/Z/12/Z)
Wellcome Trust (100140/Z/12/Z)
Medical Research Council (G9824984)
Medical Research Council (G0600717)
Medical Research Council (G0802051)
Medical Research Council (G0400192)
MRC (MC_UU_00014/1)
MRC (MC_UU_00014/2)
MRC (MC_UU_00014/3)
MRC (MC_UU_00014/5)
Identifiers
External DOI: https://doi.org/10.1016/j.cmet.2018.12.016
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287446
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