Siah2 regulates lipid uptake in adipose tissue macrophages.

In obesity, adipose tissue (AT) macrophages (ATMs) reprogram their metabolism to influence AT remodeling and function. Ubiquitin (Ub) ligases are critical in modulating the degradation of key proteins implicated in macrophage lipid metabolism. Yet, the role of Ub ligases in ATM lipid metabolism is largely unexplored. Previously, we reported that the Ub ligase Siah2 (seven in absentia homolog 2) is crucial in mediating adipogenic pathways and AT inflammation. Here, we cocultured bone marrow-derived macrophages with AT as an ex vivo model of bone marrow-derived ATMs to investigate the role of Siah2 in ATM lipid metabolism. We found that AT-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 reveal a central role for Siah2 as a lipid uptake sensor in maintaining the balance between lipid influx and degradation in ATMs.