GDF15 increases insulin action in the liver and adipose tissue via a β-adrenergic receptor-mediated mechanism

Kim A. Sjøberg, Casper M. Sigvardsen, Abdiel Alvarado-Diaz, Nicoline Resen Andersen, Mark Larance, Randy J. Seeley, Peter Schjerling, Jakob G. Knudsen, Georgios Katzilieris-Petras, Christoffer Clemmensen, Sebastian Beck Jørgensen, Katrien De Bock*, Erik A. Richter

*Corresponding author for this work
12 Citations (Scopus)

Abstract

Growth differentiation factor 15 (GDF15) induces weight loss and increases insulin action in obese rodents. Whether and how GDF15 improves insulin action without weight loss is unknown. Obese rats were treated with GDF15 and displayed increased insulin tolerance 5 h later. Lean and obese female and male mice were treated with GDF15 on days 1, 3, and 5 without weight loss and displayed increased insulin sensitivity during a euglycemic hyperinsulinemic clamp on day 6 due to enhanced suppression of endogenous glucose production and increased glucose uptake in WAT and BAT. GDF15 also reduced glucagon levels during clamp independently of the GFRAL receptor. The insulin-sensitizing effect of GDF15 was completely abrogated in GFRAL KO mice and also by treatment with the β-adrenergic antagonist propranolol and in β1,β2-adrenergic receptor KO mice. GDF15 activation of the GFRAL receptor increases β-adrenergic signaling, in turn, improving insulin action in the liver and white and brown adipose tissue.

Original languageEnglish
JournalCell Metabolism
Volume35
Issue number8
Pages (from-to)1327-1340.e5
ISSN1550-4131
DOIs
Publication statusPublished - 8 Aug 2023

Keywords

  • adrenergic receptors
  • appetite control
  • euglycemic clamp
  • GFRAL receptor
  • glucagon
  • glucose metabolism
  • insulin resistance
  • insulin sensitivity

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