Details

Autor(en) / Beteiligte

• Engström Ruud, Linda
• Font-Gironès, Ferran
• Zajdel, Joanna
• Kern, Lara
• Teixidor-Deulofeu, Júlia
• Mannerås-Holm, Louise
• Carreras, Alba
• Becattini, Barbara
• Björefeldt, Andreas
• Hanse, Eric
• Fenselau, Henning
• Solinas, Giovanni
• Brüning, Jens C.
• Wunderlich, Thomas F.
• Bäckhed, Fredrik
• Ruud, Johan

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2024-04, Vol.43 (4), p.113960-113960, Article 113960

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Chemo- or optogenetic activation of GFRAL+ neurons causes hypothermia•Acute GFRAL+ neuron activation stimulates lipid oxidation and ketogenesis•Such activation impairs skeletal muscle insulin sensitivity, resulting in hyperglycemia•GDF15 treatment acutely lowers body temperature and glucose oxidation Engström Ruud et al. find that acute activation of nausea-inducing GFRAL+ neurons not only promotes lipolysis and ketogenesis but also lowers body temperature and increases blood glucose levels by impairing skeletal muscle glucose uptake. These findings suggest that such activation mimics thermo-, gluco-, and lipid-regulatory responses to nausea and torpor.