GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans.

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Alvarez-Guaita, Anna 
Melvin, Audrey 
Rimmington, Debra 
Dattilo, Alessia 

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.

GDF15, GFRAL, conditioned taste aversion, integrated stress response, overnutrion, Adult, Animals, Cell Line, Diet, High-Fat, Energy Intake, Growth Differentiation Factor 15, Humans, Mice, Mice, Inbred C57BL, Middle Aged, Young Adult
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Cell Metab
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Elsevier BV
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)
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.