GDF15 increases insulin action in the liver and adipose tissue via a β-adrenergic receptor-mediated mechanism.
GFRAL receptor
adrenergic receptors
appetite control
euglycemic clamp
glucagon
glucose metabolism
insulin resistance
insulin sensitivity
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
08 08 2023
08 08 2023
Historique:
received:
12
12
2022
revised:
10
05
2023
accepted:
27
06
2023
medline:
11
8
2023
pubmed:
21
7
2023
entrez:
20
7
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37473755
pii: S1550-4131(23)00226-7
doi: 10.1016/j.cmet.2023.06.016
pii:
doi:
Substances chimiques
Receptors, Adrenergic, beta
0
Growth Differentiation Factor 15
0
Insulin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1327-1340.e5Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests S.B.J. is an employee of Novo Nordisk, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. R.J.S. has received research support from Novo Nordisk, Fractyl, Astra Zeneca, and Eli Lilly. R.J.S. has served as a paid consultant for Novo Nordisk, Eli Lilly, Scohia, CinRx, Fractyl, Structure Therapeutics, and Congruence Therapeutics. R.J.S. has equity in Calibrate and Rewind.