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

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

doi:10.1016/j.cmet.2018.12.016

Abstract

SummaryGDF15 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.

Highlights

GDF15 is a stress-induced cytokine and an atypical member of the transforming growth factor beta superfamily (Tsai et al, 2016)
We characterize in detail the elements of the cellular integrated stress response (ISR) that are involved in the regulation of GDF15 expression and demonstrate activation of the ISR in selected tissues of high-fat-fed mice. We show that another severe nutritional perturbation, namely provision of a lysine-deficient diet to mice, activates the ISR and increases GDF15 levels
To determine if GDF15 responds in a similar way, we studied the response of humans to established stimuli of the enteroendocrine system

Summary

Introduction

GDF15 (growth differentiation factor 15; known as macrophage inhibitory cytokine-1 [MIC-1], NAG1, PLAB, and PDF) is a stress-induced cytokine and an atypical member of the transforming growth factor beta superfamily (Tsai et al, 2016). It is predominantly expressed in the liver, lung, and kidney and, at least in humans, in large amounts in the placenta (Bottner et al, 1999; Ding et al, 2009; Fairlie et al, 1999; Lawton et al, 1997; Marjono et al, 2003; Yokoyama-Kobayashi et al, 1997) It circulates at high levels in humans (Brown et al, 2003; Ho et al, 2012; Kempf et al, 2007; Mullican and Rangwala, 2018) and serum levels are known to increase with age, smoking, intense exercise, cancer, and a range of other disease states (reviewed in Corre et al, 2013; Kleinert et al, 2018; Unsicker et al, 2013). The measurement of circulating concentrations of GDF15 is beginning to enter clinical practice as a diagnostic biomarker in mitochondrial disease and as a prognostic marker in conditions such as heart failure and certain cancers (Fujita et al, 2016; Wang et al, 2013; Wollert et al, 2017)

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