PT  - JOURNAL ARTICLE
AU  - Carla Igual Gil
AU  - Bethany M Coull
AU  - Wenke Jonas
AU  - Rachel N Lippert
AU  - Susanne Klaus
AU  - Mario Ost
TI  - Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior
AID  - 10.26508/lsa.202201495
DP  - 2022 Nov 01
TA  - Life Science Alliance
PG  - e202201495
VI  - 5
IP  - 11
4099  - https://www.life-science-alliance.org/content/5/11/e202201495.short
4100  - https://www.life-science-alliance.org/content/5/11/e202201495.full
SO  - Life Sci. Alliance2022 Nov 01; 5
AB  - 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.