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Cell Metab. 2019 Mar 5;29(3):707-718.e8. doi: 10.1016/j.cmet.2018.12.016. Epub 2019 Jan 10.

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

Author information

1
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
2
INRA, Unité de Nutrition Humaine, Université Clermont Auvergne, 63000 Clermont-Ferrand, France.
3
Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL, USA.
4
Pennington Biomedical Research Center, Baton Rouge, LA, USA.
5
Internal Medicine Research Unit, Pfizer Global R&D, 1 Portland Street, Cambridge, MA, USA.
6
School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, Leicestershire LE11 3TU, UK.
7
Department of Clinical Medicine, Aarhus University Hospital, Aarhus University, Aarhus, Denmark.
8
Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
9
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK; Cambridge Institute for Medical Research, Cambridge University, Cambridge CB2 0XY, UK.
10
Department of Physical Performance, Norwegian School of Sport Sciences, Oslo, Norway.
11
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: dbs23@medschl.cam.ac.uk.
12
Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK. Electronic address: so104@medschl.cam.ac.uk.

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:

GDF15; GFRAL; conditioned taste aversion; integrated stress response; overnutrion

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