Dataset Information

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

ABSTRACT: Muscle mitochondrial stress signals to the brain via hindbrain-specific GFRAL receptor signaling to promote hypothalamic CRH induction, which associates with GFRAL-dependent modulation of systemic energy metabolism, 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 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. Graphical Abstract

SUBMITTER: Igual Gil C

PROVIDER: S-EPMC9449705 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundPoor dietary choices may underlie known associations between having an evening diurnal preference and cardiometabolic diseases. Assessing causal links between diurnal preference and food intake is now possible in Mendelian randomization (MR) analyses.ObjectivesWe aimed to use a 2-sample MR to determine potential causal effects of genetic liability to a morning preference on food intake. We also examined potential causal effects of a morning preference on objectively captured response performances to email-administered 24-h diet recalls.MethodsWe used genetic variants associated with a morning preference from a published genome-wide association meta-analysis. Our outcomes included 61 food items with estimates from a food-frequency questionnaire in the UK Biobank (n = 361,194). For significant findings, we repeated the analysis using intake estimates from modified 24-h diet recalls in a subset of overlapping participants (n = 146,086). In addition, we examined 7 response performance outcomes, including the time and duration of responses to 24-h diet recalls (n = 123,035). MR effects were estimated using an inverse-variance weighted analysis.ResultsGenetic liability to a morning preference was associated with increased intake of 6 food items (fresh fruit, alcohol with meals, bran cereal, cereals, dried fruit, and water), decreased intake of 4 food items (beer plus cider, processed meat, other cereals [e.g., corn or frosted flakes], and full cream milk), increased temperature of hot drinks, and decreased variation in diet (PFalse Discovery Rate < 0.05). There was no evidence for an effect on coffee or tea intake. Findings for fresh fruit, beer plus cider, bran cereal, and cereal were consistent when intakes were estimated by 24-h diet recalls (P < 0.05). We also identified potential causal links between a morning preference with earlier timing and a shorter duration for completing email-administered 24-h diet recalls.ConclusionsOur findings provide evidence for a potentially causal effect of a morning preference with the increased intake of foods known to constitute a healthy diet, suggesting possible health benefits of adopting a more morning diurnal preference.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets