Nipsnap1—A Regulatory Factor Required For Long-Term Maintenance of Non-Shivering Thermogenesis

SUMMARY The molecular activation of non-shivering thermogenesis (NST) has strong potential to combat obesity and metabolic disease. However, the mechanisms surrounding the maintenance of NST once it is fully activated, remain unexplored. Here, we present 4-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like 1 (Nipsnap1) as a critical regulator of long-term thermogenic maintenance in brown adipose tissue (BAT). Nipsnap1 localizes to the mitochondrial matrix and increases its transcript and protein levels in response to both chronic cold and β 3 adrenergic signaling. Through the generation of BAT-specific Nipsnap1 knockout mice (N1-KO), we show that these mice are unable to sustain activated energy expenditure and fail to protect their body temperature in the face of an extended cold challenge. Mechanistically, we demonstrate that Nipsnap1 integrates with lipid metabolism and BAT-specific ablation of Nipsnap1 leads to severe defects in β-oxidation capacity. Our findings identify Nipsnap1 as a potent regulator of long-term NST maintenance.