Drug‐like sphingolipid SH‐BC‐893 opposes ceramide‐induced mitochondrial fission and corrects diet‐induced obesity

Ceramide‐induced mitochondrial fission drives high‐fat diet (HFD)‐induced obesity. However, molecules targeting mitochondrial dynamics have shown limited benefits in murine obesity models. Here, we reveal that these compounds are either unable to block ceramide‐induced mitochondrial fission or require extended incubation periods to be effective. In contrast, targeting endolysosomal trafficking events important for mitochondrial fission rapidly and robustly prevented ceramide‐induced disruptions in mitochondrial form and function. By simultaneously inhibiting ARF6‐ and PIKfyve‐dependent trafficking events, the synthetic sphingolipid SH‐BC‐893 blocked palmitate‐ and ceramide‐induced mitochondrial fission, preserved mitochondrial function, and prevented ER stress in vitro. Similar benefits were observed in the tissues of HFD‐fed mice. Within 4 h of oral administration, SH‐BC‐893 normalized mitochondrial morphology in the livers and brains of HFD‐fed mice, improved mitochondrial function in white adipose tissue, and corrected aberrant plasma leptin and adiponectin levels. As an interventional agent, SH‐BC‐893 restored normal body weight, glucose disposal, and hepatic lipid levels in mice consuming a HFD. In sum, the sphingolipid analog SH‐BC‐893 robustly and acutely blocks ceramide‐induced mitochondrial dysfunction, correcting diet‐induced obesity and its metabolic sequelae.