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.
Authors
- Kotaro Yoshimura (ORCID: https://orcid.org/0000-0002-7152-5475)
- Momoko Horikoshi (ORCID: https://orcid.org/0000-0002-7103-2267)
- Hiroyuki Aburatani (ORCID: https://orcid.org/0000-0003-0438-1544)
- Kotaro Soeda (ORCID: https://orcid.org/0000-0001-9942-5081)
- Yukiko Okazaki
- Yasuyuki Seto (ORCID: https://orcid.org/0000-0002-6953-8752)
- Toshimasa Yamauchi (ORCID: https://orcid.org/0000-0003-4827-6404)
- Takayoshi Sasako (ORCID: https://orcid.org/0000-0002-7644-309X)
- Takashi Kadowaki (ORCID: https://orcid.org/0000-0002-5428-3582)
- Motoharu Awazawa
- Matthias Blüher (ORCID: https://orcid.org/0000-0003-0208-2065)
- Maya Matsushita
- Kenta Kobayashi (ORCID: https://orcid.org/0000-0002-7389-3693)
- Aya Iwane
- Kohjiro Ueki (ORCID: https://orcid.org/0000-0003-1523-8102)
- Naoki Kobayashi (ORCID: https://orcid.org/0000-0002-0537-0604)
- Kazuo Hara (ORCID: https://orcid.org/0000-0002-2744-7182)
- Nobuyuki Itoh
Institutions
- Jikei University School of Medicine (JP)
- Tokyo University of Technology (JP)
- Tokyo University of Science (JP)
- The Graduate University for Advanced Studies, SOKENDAI (JP)
- Kyoto University (JP)
- Kyoto Pharmaceutical University (JP)
- National Center for Global Health and Medicine (JP)
- National Institute for Physiological Sciences (JP)
- Toranomon Hospital (JP)
- The University of Tokyo (JP)
- Leipzig University (DE)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1038/s41467-025-58836-w
- Citations
- 2
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Japan Foundation for Applied Enzymology
- Japan Agency for Medical Research and Development
- National Center for Global Health and Medicine
- Deutsche Forschungsgemeinschaft
- Ministry of Education, Culture, Sports, Science and Technology
- Ministry of Health, Labour and Welfare
- Fujita Health University
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency