In obesity, adipose tissue macrophages (ATMs) reprogram their metabolism to influence adipose tissue remodeling and function. Ubiquitin ligases are critical in modulating degradation of key proteins implicated in macrophage lipid metabolism. Yet, the role of ubiquitin ligases in ATM lipid metabolism is largely unexplored. Previously, we reported that the ubiquitin ligase Siah2 is crucial in mediating adipogenic pathways and adipose tissue inflammation. Here, we co-cultured bone marrow-derived macrophages with adipose tissue as an ex vivo model of bone marrow-derived ATMs to investigate Siah2's role in ATM lipid metabolism. We found that adipose tissue- induced lipid accumulation in ATMs was exacerbated by Siah2 deficiency via increased CD36-mediated lipid uptake and reduced lipid delivery to lysosomes. Together, these changes contributed to excessive lipid accumulation, lipid peroxidation and an inflammatory phenotype. Our data reveals a central role for Siah2 as a lipid uptake sensor in maintaining the balance between lipid influx and degradation in ATMs.
Ghosh et al. (Sun,) studied this question.