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

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.