Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor
Linda Engström Ruud,
Ferran Font-Gironès,
Joanna Zajdel,
Lara Kern,
Júlia Teixidor-Deulofeu,
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
Affiliations
Linda Engström Ruud
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Ferran Font-Gironès
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Joanna Zajdel
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Lara Kern
Max Planck Institute for Metabolism Research, Cologne, Germany
Júlia Teixidor-Deulofeu
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Louise Mannerås-Holm
Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
Alba Carreras
Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
Barbara Becattini
Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
Andreas Björefeldt
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Eric Hanse
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Henning Fenselau
Max Planck Institute for Metabolism Research, Cologne, Germany
Giovanni Solinas
Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
Jens C. Brüning
Max Planck Institute for Metabolism Research, Cologne, Germany
Thomas F. Wunderlich
Max Planck Institute for Metabolism Research, Cologne, Germany
Fredrik Bäckhed
Department of Molecular and Clinical Medicine, The Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden; Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden
Johan Ruud
Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Corresponding author
Summary: 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.
