Lipophagy Enhances Fat Graft Retention by Stimulating Dedifferentiation of Mature Adipocytes and Modulating Inflammation

Background: Maintaining lipid metabolic homeostasis is essential for cells to respond to environmental stresses, ensure survival, and preserve functionality. Lipophagy is a form of autophagy in which intracellular lysosomes target and degrade lipid droplets. The authors hypothesize that pharmacologically enhancing or disrupting lipophagy could either improve or impair the retention rates of fat grafts. Methods: Human fat graft nodules, retained for 6 months, were collected through surgical procedures for analysis. In addition, a mouse fat graft model was established by mixing fragmented adipose tissue with the autophagy inducer rapamycin, the autophagy inhibitor 3-methyladenine, or phosphate-buffered saline, and subcutaneously implanting them into the bilateral lower backs of mice for localized activation or inhibition of lipophagy. Samples were collected at various time points for morphologic, histologic, transcriptomic, and gene expression analysis. Results: A significant increase in lipophagy was demonstrated in both human and mouse fat grafts. Rapamycin-induced up-regulation of lipophagy promoted long-term retention of mouse fat grafts and resulted in fewer cysts and reduced fibrosis. Lipophagy activation facilitated the dedifferentiation of mature adipocytes and adipogenesis. Moreover, lipophagy enhanced the metabolism of oil droplets in macrophages. Activation of lipophagy also reduced long-term macrophage infiltration and collagen deposition in fat grafts and simultaneously increased the proportion of M2 macrophages. Conclusions: Lipophagy was activated following fat grafting. Lipophagy improves fat graft retention and quality by stimulating the dedifferentiation of mature adipocytes, promoting oil metabolism, and reducing inflammation. Thus, lipophagy serves as a crucial integrative point connecting lipid metabolism, regeneration, and immunity in fat grafts. Clinical Relevance Statement: Rapamycin-induced upregulation of lipophagy enhances fat graft retention by stimulating dedifferentiation of mature adipocytes and modulating inflammation.