Elevated 1-deoxysphingolipids in adipose tissue promote inflammation

Chronic adipose tissue inflammation is a hallmark of numerous metabolic disorders, yet its initial triggers remain elusive. Here, we discover that excessive accumulation of toxic 1-deoxysphingolipid (DoxSL), a non-canonical sphingolipid species, in adipose tissue leads to the local release of pro-inflammatory cytokines. Mechanistically, DoxSL is sequestered in lipid droplets within adipose tissue to mitigate cytotoxicity under physiological conditions, but its levels are significantly elevated in states such as obesity and aging. A targeted increase in DoxSL triggers adipose tissue inflammation and macrophage infiltration via activation of the NF-?B pathway. Notably, reducing DoxSL levels through pharmacological treatment attenuates inflammation in obese mice. These findings uncover a previously unknown metabolic mechanism and emphasize a critical role of lipids in driving adipose tissue inflammation. Overall design: RNA seq profiling of differentiated adipocyte with DMSO or DoxSa treatment on Day6