Activation of GFRAL+ Neurons Induces Hypothermia and Glucoregulatory Responses Associated with Nausea and Torpor

GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment and may mediate metformin effects by long-term GDF15-GFRAL agonism. If GFRAL+ neurons acutely regulate glucose and energy homeostasis is however underexplored. Here, we report that cell-specific activation of GFRAL+ neurons using a variety of techniques causes a torpor-like state, including hypothermia, the release of stress hormones, a shift from glucose to lipid oxidation, and impaired insulin sensitivity, glucose tolerance and skeletal muscle glucose uptake but augmented glucose uptake in visceral fat. Metabolomic analysis of blood and transcriptomics of muscle and fat indicate alterations in ketogenesis, insulin signaling, adipose tissue differentiation and mitogenesis, or energy fluxes. Our findings reveal that acute GFRAL+ neuron activation induces endocrine and gluco- and thermoregulatory responses associated with nausea and torpor. While chronic activation of GFRAL signaling promotes weight loss in obesity, these results show that acute activation of GFRAL+ neurons causes hypothermia and hyperglycemia. Overall design: To investigate the impact of chemogenetic GFRAL+ neuron activation on gene expression in tissues that showed lowered (quadriceps) or increased (perigonadal white adipose tissue; pgWAT) glucose uptake, we performed RNAseq on RNA isolated from these tissues. Samples were collected from hM3DGq male mice that were either Gfral Cre-positive or negative. For quadriceps, material was obtained from CNO-injected clamped mice, for pgWAT the material was obtained at 1h or 6h after CNO-injection (activation of Gfral neurons). Replicates: For quadriceps, 10 vs 10; for pgWAT CNO 1h, 9 vs 9; for pgWAT CNO 6h, 6 vs 6.