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Peer-reviewedCC BY-NCScience Advances

ALIX-dependent small extracellular vesicles from tissue-resident mesenchymal cells regulate pancreatic β cell proliferation in obesity

  • Yuhei Uehara1
  • Hirofumi Nagao1,2
  • Aoki Tobimatsu1
  • Keitaro Kawada1
  • Shunsuke Shiode1
  • Emi Horitani1
  • Yoshinari Obata1
  • Shiro Fukuda1
  • Yuya Fujishima1,2
  • Shunbun Kita1
  • Hitoshi Nishizawa1
  • Iichiro Shimomura1
  1. 1Department of Metabolic Medicine, Graduate School of Medicine, The University of Osaka, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
  2. 2Department of Metabolism and Atherosclerosis, Graduate School of Medicine, The University of Osaka, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
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Abstract

Cells throughout the body release small extracellular vesicles (sEVs), including exosomes, that function as modulators of both local and systemic metabolism. Using mice in which ALIX, a key regulator of sEV biogenesis, was selectively deleted in PDGFRα + mesenchymal progenitors (Pα-ALIXKO mice), we demonstrate a critical role for mesenchymal sEV production in metabolic regulation. In high-fat diet–induced obesity, Pα-ALIXKO mice exhibited reduced weight gain and smaller subcutaneous adipocytes compared with control mice. Despite similar insulin sensitivity, these mice showed impaired glucose tolerance, which was associated with reduced pancreatic β cell area and smaller islets. sEVs isolated from conditioned media of knockout (KO)–derived mesenchymal stem cells (MSCs) exhibited a reduced capacity to promote β cell proliferation. Furthermore, MSCs isolated from subcutaneous adipose tissue of KO mice showed elevated mRNA expression of inflammatory genes. Together, these findings indicate that ALIX in tissue-resident mesenchymal progenitors is required for pancreatic β cell proliferation and glucose homeostasis in obesity.

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Cite

BibTeXRIS
BibTeX
@article{uehara2026alixdependent,
  title = {{ALIX-dependent small extracellular vesicles from tissue-resident mesenchymal cells regulate pancreatic β cell proliferation in obesity}},
  author = {Yuhei Uehara and Hirofumi Nagao and Aoki Tobimatsu and Keitaro Kawada and Shunsuke Shiode and Emi Horitani and Yoshinari Obata and Shiro Fukuda and Yuya Fujishima and Shunbun Kita and Hitoshi Nishizawa and Iichiro Shimomura},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aei1333},
  url = {https://www.science.org/doi/10.1126/sciadv.aei1333},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - ALIX-dependent small extracellular vesicles from tissue-resident mesenchymal cells regulate pancreatic β cell proliferation in obesity
AU  - Yuhei Uehara
AU  - Hirofumi Nagao
AU  - Aoki Tobimatsu
AU  - Keitaro Kawada
AU  - Shunsuke Shiode
AU  - Emi Horitani
AU  - Yoshinari Obata
AU  - Shiro Fukuda
AU  - Yuya Fujishima
AU  - Shunbun Kita
AU  - Hitoshi Nishizawa
AU  - Iichiro Shimomura
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.aei1333
UR  - https://www.science.org/doi/10.1126/sciadv.aei1333
AB  - Cells throughout the body release small extracellular vesicles (sEVs), including exosomes, that function as modulators of both local and systemic metabolism. Using mice in which ALIX, a key regulator of sEV biogenesis, was selectively deleted in PDGFRα + mesenchymal progenitors (Pα-ALIXKO mice), we demonstrate a critical role for mesenchymal sEV production in metabolic regulation. In high-fat diet–induced obesity, Pα-ALIXKO mice exhibited reduced weight gain and smaller subcutaneous adipocytes compared with control mice. Despite similar insulin sensitivity, these mice showed impaired glucose tolerance, which was associated with reduced pancreatic β cell area and smaller islets. sEVs isolated from conditioned media of knockout (KO)–derived mesenchymal stem cells (MSCs) exhibited a reduced capacity to promote β cell proliferation. Furthermore, MSCs isolated from subcutaneous adipose tissue of KO mice showed elevated mRNA expression of inflammatory genes. Together, these findings indicate that ALIX in tissue-resident mesenchymal progenitors is required for pancreatic β cell proliferation and glucose homeostasis in obesity.
SN  - 2375-2548
ER  -