Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior
Growth differentiation factor 15 (GDF15) is a mitochondrial stress-induced cytokine that modulates energy balance in an endocrine manner. However, the importance of its brainstem-restricted receptor GDNF family receptor alpha-like (GFRAL) to mediate endocrine GDF15 signaling to the brain upon mitoch...
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Published in | Life science alliance Vol. 5; no. 11; p. e202201495 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Life Science Alliance LLC
01.11.2022
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Online Access | Get full text |
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Summary: | Growth differentiation factor 15 (GDF15) is a mitochondrial stress-induced cytokine that modulates energy balance in an endocrine manner. However, the importance of its brainstem-restricted receptor GDNF family receptor alpha-like (GFRAL) to mediate endocrine GDF15 signaling to the brain upon mitochondrial dysfunction is still unknown. Using a mouse model with muscle-specific mitochondrial dysfunction, we here show that GFRAL is required for activation of systemic energy metabolism via daytime-restricted anorexia but not responsible for muscle wasting. We further find that muscle mitochondrial stress response involves a GFRAL-dependent induction of hypothalamic corticotropin-releasing hormone, without elevated corticosterone levels. Finally, we identify that GFRAL signaling governs an anxiety-like behavior in male mice with muscle mitochondrial dysfunction, with females showing a less robust GFRAL-dependent anxiety-like phenotype. Together, we here provide novel evidence of a mitochondrial stress-induced muscle–brain crosstalk via the GDF15-GFRAL axis to modulate food intake and anxiogenic behavior. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Susanne Klaus and Mario Ost contributed equally to this work. |
ISSN: | 2575-1077 2575-1077 |
DOI: | 10.26508/lsa.202201495 |