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

Naoki Kobayashi, Yukiko Okazaki, Aya Iwane, Kazuo Hara, Momoko Horikoshi, Motoharu Awazawa, Kotaro Soeda, Maya Matsushita, Takayoshi Sasako, Kotaro Yoshimura, Nobuyuki Itoh, Kenta Kobayashi, Yasuyuki Seto, Toshimasa Yamauchi, Hiroyuki Aburatani, Matthias Blüher, Takashi Kadowaki and Kohjiro Ueki ()
Additional contact information
Naoki Kobayashi: National Center for Global Health and Medicine
Yukiko Okazaki: National Center for Global Health and Medicine
Aya Iwane: The University of Tokyo
Kazuo Hara: The University of Tokyo
Momoko Horikoshi: The University of Tokyo
Motoharu Awazawa: National Center for Global Health and Medicine
Kotaro Soeda: National Center for Global Health and Medicine
Maya Matsushita: National Center for Global Health and Medicine
Takayoshi Sasako: National Center for Global Health and Medicine
Kotaro Yoshimura: The University of Tokyo
Nobuyuki Itoh: Kyoto University
Kenta Kobayashi: National Institute for Physiological Sciences
Yasuyuki Seto: The University of Tokyo
Toshimasa Yamauchi: The University of Tokyo
Hiroyuki Aburatani: The University of Tokyo
Matthias Blüher: University of Leipzig
Takashi Kadowaki: The University of Tokyo
Kohjiro Ueki: National Center for Global Health and Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-58836-w

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