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Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia

View ORCID ProfileCarla Igual Gil, Bethany M. Coull, View ORCID ProfileWenke Jonas, View ORCID ProfileRachel Lippert, View ORCID ProfileMario Ost, View ORCID ProfileSusanne Klaus
doi: https://doi.org/10.1101/2021.09.22.461199
Carla Igual Gil
1Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
2Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany
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Bethany M. Coull
3Department of Neurocircuit Development and Function, German Institute of Human Nutrition
7NeuroCure Cluster of Excellence, Charité Universitätsmedizin, Berlin, Germany
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Wenke Jonas
4Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
5German Center for Diabetes Research, 85764 München-Neuherberg, Germany
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Rachel Lippert
3Department of Neurocircuit Development and Function, German Institute of Human Nutrition
5German Center for Diabetes Research, 85764 München-Neuherberg, Germany
7NeuroCure Cluster of Excellence, Charité Universitätsmedizin, Berlin, Germany
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Mario Ost
1Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
6Institute of Anatomy, University of Leipzig, 04103, Leipzig, Germany
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  • For correspondence: klaus@dife.de mario.ost@dife.de
Susanne Klaus
1Department of Physiology of Energy Metabolism, German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), 14558 Nuthetal, Germany
2Institute of Nutritional Science, University of Potsdam, 14469 Potsdam, Germany
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  • For correspondence: klaus@dife.de mario.ost@dife.de
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Abstract

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that modulates food intake and energy metabolism. Until now, most mechanistic studies on GDF15 rely on pharmacological interventions using exogenous GDF15, but little is known about its mode of action when induced both chronically and endogenously. Mitochondrial stress is one of the most described physiological conditions that induces GDF151, and therefore an important model to study the underlying mechanisms of endogenous GDF15’s action. Here, using a mouse model of mitochondrial dysfunction via elevated respiratory uncoupling in skeletal muscle, we show a circadian oscillation of muscle-derived GDF15 to promote a daytime-restricted anorexia without signs of nausea or reduced physical activity, contrary to findings using recombinant GDF152–5. We find that mitochondrial stress-induced GDF15 associates with increased anxiety and hypothalamic corticotropin releasing hormone (CRH) induction, without further activation of the hypothalamic-pituitary-adrenal (HPA) axis and corticosterone response. Strikingly, the daytime-restricted anorexia, lean phenotype, systemic shift in substrate metabolism and anxiety-like behavior are completely abolished in conditions of mitochondrial stress coupled with genetic ablation of the GDF15 receptor GDNF receptor alpha-like (GFRAL), which is predominantly expressed in the hindbrain. Finally, we demonstrate that stress-induced GDF15-GFRAL signaling is required for hypothalamic CRH induction to control diurnal food intake in a CRH-receptor 1 (CRHR1)-dependent manner. With this, we uncover for the first time a molecular target of the GDF15-GFRAL axis that links anxiolytic and anorectic behavior as downstream effects of the chronic activation of this pathway by mitochondrial stress.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted September 24, 2021.
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Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia
Carla Igual Gil, Bethany M. Coull, Wenke Jonas, Rachel Lippert, Mario Ost, Susanne Klaus
bioRxiv 2021.09.22.461199; doi: https://doi.org/10.1101/2021.09.22.461199
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Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia
Carla Igual Gil, Bethany M. Coull, Wenke Jonas, Rachel Lippert, Mario Ost, Susanne Klaus
bioRxiv 2021.09.22.461199; doi: https://doi.org/10.1101/2021.09.22.461199

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