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

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.