Mitochondrial stress-induced GFRAL signaling controls diurnal food intake and anxiety-like behavior

• Published in: Life science alliance 2022-11, Vol.5 (11), p.e202201495
• Main Authors: Igual Gil, Carla, Coull, Bethany M, Jonas, Wenke, Lippert, Rachel N, Klaus, Susanne, Ost, Mario
• Format: Article
• Language: English
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202201495

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.