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

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.
Competing Interests: 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.
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