Cold exposure activates brown adipose tissue (BAT), to alleviate metabolic disorders. However, the mechanisms underlying the regulation of mitochondrial lipid droplet contact (MLC) in BAT and their association with these benefits remain unclear. Here, we identify liver-derived β-hydroxybutyrate (BHB) as a key mediator in driving MLC formation in BAT. Mechanistically, BHB directly targets at the GLY-67 residue of RAB10, enhancing its interaction with PLIN5 to form the RAB10–PLIN5 complex, which facilitates MLC. This interaction was validated using SPIDER and biotin-labeled pull-down assays. Functionally, BHB treatment reduces lipotoxicity and improves metabolic health in diet-induced obese mice. These findings establish BHB as a critical link between BAT MLC and the systemic metabolic benefits, highlighting the RAB10–PLIN5 complex as a therapeutic target for obesity and hepatic steatosis. Furthermore, this work underscores the broader significance of cold-induced metabolic adaptations for combating metabolic diseases.

β-Hydroxybutyrate  /  Mitochondrial lipid droplet contact  /  RAB10-PLIN5 complex  /  Cold exposure  /  HADHA  /  Liver-brown fat communication  /  Lipotoxicity  /  Hepatic steatosis