Activin B improves glucose metabolism via induction of Fgf21 and hepatic glucagon resistance.

Orchestrated hormonal interactions in response to feeding and fasting play a pivotal role in regulating glucose homeostasis. Here, we show that in obesity, the production of follistatin-like 3 (FSTL3), an endogenous inhibitor of Activin B, in adipose tissue is increased in both mice and humans. The knockdown of FSTL3 improves insulin sensitivity and glucose tolerance in diabetic obese db/db mice. Notably, the overexpression of Activin B, a member of the TGFβ superfamily that is induced in liver sinusoidal endothelial cells by fasting, exerts multiple metabolically beneficial effects, including improvement of insulin sensitivity, suppression of hepatic glucose production, and enhancement of glucose-stimulated insulin secretion, all of which are attenuated by the overexpression of FSTL3. Activin B increases insulin sensitivity and reduces fat by inducing fibroblast growth factor 21 (FGF21) while suppressing glucagon action in the liver by increasing phosphodiesterase 4 B (PDE4B), leading to hepatic glucagon resistance and resultant hyperglucagonemia. Activin B-induced hyperglucagonemia enhances glucose-stimulated insulin secretion by stimulating glucagon-like peptide-1 (GLP-1) receptor in pancreatic β-cells. Thus, enhancing the action of Activin B which improves multiple components of the pathogenesis of diabetes may be a promising strategy for diabetes treatment.