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

Satish Patel; Anna Alvarez-Guaita; Audrey Melvin; Debra Rimmington; Alessia Dattilo; Emily L Miedzybrodzka; Irene Cimino; Anne-Catherine Maurin; Geoffrey P Roberts; Claire L Meek; Samuel Virtue; Lauren M Sparks; Stephanie A Parsons; Leanne M Redman; George A Bray; Alice P Liou; Rachel M Woods; Sion A Parry; Per B Jeppesen; Anders J Kolnes; Heather P Harding; David Ron; Antonio Vidal-Puig; Frank Reimann; Fiona M Gribble; Carl J Hulston; I Sadaf Farooqi; Steven R Smith; Jorgen Jensen; Danna Breen; Zhidan Wu; Anthony P Coll; Bei B Zhang; David B Savage; Stephen O'Rahilly

doi:10.1016/j.cmet.2018.12.016

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

Satish Patel, Anna Alvarez-Guaita, Audrey Melvin, Debra Rimmington, Alessia Dattilo, Emily L Miedzybrodzka, Irene Cimino, Anne-Catherine Maurin, Geoffrey P Roberts, Claire L Meek, Samuel Virtue, Lauren M Sparks, Stephanie A Parsons, Leanne M Redman, George A Bray, Alice P Liou, Rachel M Woods, Sion A Parry, Per B Jeppesen, Anders J KolnesHeather P Harding, David Ron, Antonio Vidal-Puig, Frank Reimann, Fiona M Gribble, Carl J Hulston, I Sadaf Farooqi, Steven R Smith, Jorgen Jensen, Danna Breen, Zhidan Wu, Anthony P Coll, Bei B Zhang, David B Savage, Stephen O'Rahilly

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	707-718.e8
Journal	Cell metabolism
Volume	29
Issue number	3
DOIs	https://doi.org/10.1016/j.cmet.2018.12.016
Publication status	Published - 5 Mar 2019

Keywords

Adult
Animals
Cell Line
Diet, High-Fat/methods
Energy Intake/physiology
Growth Differentiation Factor 15/metabolism
Humans
Mice
Mice, Inbred C57BL
Middle Aged
Young Adult

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Patel, S., Alvarez-Guaita, A., Melvin, A., Rimmington, D., Dattilo, A., Miedzybrodzka, E. L., Cimino, I., Maurin, A.-C., Roberts, G. P., Meek, C. L., Virtue, S., Sparks, L. M., Parsons, S. A., Redman, L. M., Bray, G. A., Liou, A. P., Woods, R. M., Parry, S. A., Jeppesen, P. B., ... O'Rahilly, S. (2019). GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans. Cell metabolism, 29(3), 707-718.e8. https://doi.org/10.1016/j.cmet.2018.12.016

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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 = "Adult, Animals, Cell Line, Diet, High-Fat/methods, Energy Intake/physiology, Growth Differentiation Factor 15/metabolism, Humans, Mice, Mice, Inbred C57BL, Middle Aged, Young Adult",

author = "Satish Patel and Anna Alvarez-Guaita and Audrey Melvin and Debra Rimmington and Alessia Dattilo and Miedzybrodzka, {Emily L} and Irene Cimino and Anne-Catherine Maurin and Roberts, {Geoffrey P} and Meek, {Claire L} and Samuel Virtue and Sparks, {Lauren M} and Parsons, {Stephanie A} and Redman, {Leanne M} and Bray, {George A} and Liou, {Alice P} and Woods, {Rachel M} and Parry, {Sion A} and Jeppesen, {Per B} and Kolnes, {Anders J} and Harding, {Heather P} and David Ron and Antonio Vidal-Puig and Frank Reimann and Gribble, {Fiona M} and Hulston, {Carl J} and Farooqi, {I Sadaf} and Smith, {Steven R} and Jorgen Jensen and Danna Breen and Zhidan Wu and Coll, {Anthony P} and Zhang, {Bei B} and Savage, {David B} and Stephen O'Rahilly",

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doi = "10.1016/j.cmet.2018.12.016",

language = "English",

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journal = "Cell metabolism",

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Patel, S, Alvarez-Guaita, A, Melvin, A, Rimmington, D, Dattilo, A, Miedzybrodzka, EL, Cimino, I, Maurin, A-C, Roberts, GP, Meek, CL, Virtue, S, Sparks, LM, Parsons, SA, Redman, LM, Bray, GA, Liou, AP, Woods, RM, Parry, SA, Jeppesen, PB, Kolnes, AJ, Harding, HP, Ron, D, Vidal-Puig, A, Reimann, F, Gribble, FM, Hulston, CJ, Farooqi, IS, Smith, SR, Jensen, J, Breen, D, Wu, Z, Coll, AP, Zhang, BB, Savage, DB & O'Rahilly, S 2019, 'GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans', Cell metabolism, vol. 29, no. 3, pp. 707-718.e8. https://doi.org/10.1016/j.cmet.2018.12.016

TY - JOUR

T1 - GDF15 Provides an Endocrine Signal of Nutritional Stress in Mice and Humans

AU - Patel, Satish

AU - Alvarez-Guaita, Anna

AU - Melvin, Audrey

AU - Rimmington, Debra

AU - Dattilo, Alessia

AU - Miedzybrodzka, Emily L

AU - Cimino, Irene

AU - Maurin, Anne-Catherine

AU - Roberts, Geoffrey P

AU - Meek, Claire L

AU - Virtue, Samuel

AU - Sparks, Lauren M

AU - Parsons, Stephanie A

AU - Redman, Leanne M

AU - Bray, George A

AU - Liou, Alice P

AU - Woods, Rachel M

AU - Parry, Sion A

AU - Jeppesen, Per B

AU - Kolnes, Anders J

AU - Harding, Heather P

AU - Ron, David

AU - Vidal-Puig, Antonio

AU - Reimann, Frank

AU - Gribble, Fiona M

AU - Hulston, Carl J

AU - Farooqi, I Sadaf

AU - Smith, Steven R

AU - Jensen, Jorgen

AU - Breen, Danna

AU - Wu, Zhidan

AU - Coll, Anthony P

AU - Zhang, Bei B

AU - Savage, David B

AU - O'Rahilly, Stephen

PY - 2019/3/5

Y1 - 2019/3/5

N2 - 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.

AB - 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.

KW - Adult

KW - Animals

KW - Cell Line

KW - Diet, High-Fat/methods

KW - Energy Intake/physiology

KW - Growth Differentiation Factor 15/metabolism

KW - Humans

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Young Adult

UR - https://www.sciencedirect.com/science/article/pii/S1550413118307538?via%3Dihub

U2 - 10.1016/j.cmet.2018.12.016

DO - 10.1016/j.cmet.2018.12.016

M3 - Article

C2 - 30639358

SN - 1550-4131

VL - 29

SP - 707-718.e8

JO - Cell metabolism

JF - Cell metabolism

IS - 3

ER -

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

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