Exosome trafficking is a key regulator of adipocyte thermogenesis.

Activation of beige adipocytes enhances energy expenditure and promotes metabolic health, presenting a promising approach for combating obesity and diabetes. As part of this process, thermogenesis, fueled by uncoupled mitochondrial respiration, plays a central role in converting calories into thermal energy, thereby preventing their storage as fat. Here, we identify exosome trafficking as an intrinsic regulator of thermogenic adipocyte function. Exosomes are small extracellular vesicles that mediate cell-cell and intracellular communication by transporting regulatory cargo, including microRNAs, proteins, and lipids. Using both human cells and mouse models, we show that thermogenic activation of beige adipocytes promotes the rapid release of exosomes enriched in microRNAs known to suppress thermogenic programs. Consistent with a functional role for exosome trafficking, genetic or pharmacological disruption of this pathway attenuated thermogenesis, whereas enhancing exosome release amplified thermogenic output. Mice deficient in the exosome trafficking regulator Rab27a exhibit reduced energy expenditure in response to both cold exposure and β3-adrenergic stimulation, while enhancement of exosome release promotes thermogenic activity in vitro and in vivo. These findings establish exosome trafficking as a key contributor to thermogenic adipocyte function and thermogenic remodeling, highlighting an intracellular mechanism that may be leveraged to enhance energy expenditure and treat obesity-related metabolic diseases.