Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor

• DOI: 10.1016/j.celrep.2024.113960
• Publication Date: 2024-03-19T17:54:38Z
• Authors: Linda Engström Ruud; Ferran Font-Gironès; Joanna Zajdel; Lara Kern; Júlia Teixidor-De...; Louise Mannerås-Holm; Alba Carreras; Barbara Becattini; Andreas Björefeldt; Eric Hanse; Henning Fenselau; Giovanni Solinas; Jens C. Brüning; Thomas F. Wunderlich; Fredrik Bäckhed; Johan Ruud
• Keywords: Neurons; Male; 0301 basic medicine; QH301-705.5; Torpor; Nausea; Hypothermia; CP: Metabolism; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Glucose; CP: Neuroscience; Animals; Insulin; Biology (General); Insulin Resistance; Muscle, Skeletal; Signal Transduction

GFRAL-expressing neurons actuate aversion and nausea, are targets for obesity treatment, and may mediate metformin effects by long-term GDF15-GFRAL agonism. Whether 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, and energy fluxes. Our findings indicate 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.