From Gut to Fat: Intestinal Epithelial Exosomes Target PDGFRα⁺ Progenitors to Promote Lipogenesis and Counteract...

Age-related subcutaneous adipose tissue (SAT) atrophy is a hallmark of aging, contributing to metabolic dysfunction and systemic aging. The mechanisms underlying SAT atrophy and potential therapeutic strategies remain poorly understood. Here, we report that small intestinal epithelium-derived exosomes (SI-Exos) mediate gut-adipose communication and play a pivotal role in age-related SAT remodeling. We found that the miRNA cargo of SI-Exos undergoes significant age-related changes. Administration of young SI-Exos to aged mice enhanced lipid droplet formation, reversed SAT atrophy, and reduced inflammation in visceral adipose tissue (VAT). These beneficial effects were mediated by young SI-Exos targeting PDGFRα⁺ progenitor cells, the major adipocyte precursors in SAT. Mechanistically, young SI-Exos were enriched with miR-379-5p, which targeted Usp34, a negative regulator of lipogenesis. Inhibition of Usp34 downregulated the Wnt/β-catenin pathway, promoting lipid droplet formation and differentiation of PDGFRα⁺ progenitor cells. Single-cell RNA sequencing analysis further confirmed that young SI-Exos enhanced lipid transport and synthesis in SAT cell populations. Additionally, NK cells were increased. Our findings reveal a previously unrecognized role of SI-Exos in regulating SAT progenitor cell dynamics through the miR-379-5p/Usp34/Wnt/β-catenin axis, offering a potential therapeutic strategy for combating age-associated SAT atrophy and promoting healthy aging.