Molecular Mechanisms of Adipose Tissue Survival during Severe Hypoxia: Implications for Autologous Fat Graft Performance

BACKGROUND: Variable retention outcomes remain a significant issue in autologous fat grafting procedures. Among seemingly similar patients, using identical harvesting procedures, variability in graft retention is noted. Recent data suggest that the inherent characteristics of donor adipose tissue dictate graft healing outcomes. The goal of this study was to elucidate intrinsic qualities of human adipose tissue that confer resistance to ischemic stress to therapeutically target such mechanisms and improve overall results of fat grafts. METHODS: Whole fat from 5 female patients was cultured in vitro under severe (1% O(2)) and mild (8% O(2)) hypoxic conditions. Microarray analysis of 44 hypoxia-related genes was performed. Perilipin was used to visualize viable adipocytes. Macrophage phenotypes were identified using PCR. RESULTS: Analysis of adipocyte survival with perilipin suggested improved viability for tissue obtained from high BMI donors. Microarray data revealed a significant positive correlation for induced expression of ANGPTL4, a survival gene, and subject BMI (P = 0.0313) during hypoxic conditions whereas HIF1α and HIF2α genes were negatively correlated with donor BMI (P = 0.0003 and 0.0303). Interestingly, induced differentiation of proinflammatory M1 macrophages was negatively correlated with BMI under hypoxia (P = 0.0177). CONCLUSIONS: The innate resilience of adipocytes to hypoxia and relative macrophage activation play a crucial role in fat graft retention. This study suggests that adipose tissue from high BMI donors demonstrates greater resistance to hypoxia-induced apoptosis associated with an increased expression of ANGPTL4. Therefore, therapeutic interventions that target this factor may improve clinical adipose graft survival.