Adipocyte lipolysis activates epithelial stem cells for hair regeneration through fatty acid metabolic signaling.

Adipocytes as vital energy reservoirs respond to systemic metabolic demands by storing or releasing lipids. Whether they can promote tissue regeneration through local metabolic communication remains unclear. We found that after skin injury, macrophages quickly infiltrate dermal adipose tissue, where they promote free fatty acid release from adipocytes via serum amyloid A3-dependent lipolysis, which, in turn, promotes hair regrowth. Epithelial hair follicle stem cells (eHFSCs) absorb the released monounsaturated fatty acids via fatty acid translocase CD36 and activate the transcriptional coactivator Pgc1-α. Downstream of Pgc1-α, increased fatty acid oxidation and mitochondrial biogenesis enhance energy production, enabling eHFSCs to exit quiescence. Topical treatment of monounsaturated fatty acids suffices to promote hair growth by activating eHFSCs. Our findings demonstrate a macrophage-to-adipocyte-to-hair follicle axis that promotes tissue-level regeneration via short-range metabolic signaling through free fatty acids. Analogous regeneration-facilitating mechanisms elicited by injury-induced panniculitis may operate in other adipose-rich organs.