From Gut to Fat: Intestinal Epithelial Exosomes Target PDGFRα ⁺ Progenitors to Promote Lipogenesis and Counteract Subcutaneous Adipose Tissue Atrophy in Aging

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.