Thermogenesis is enhanced not only by cold exposure but also by feeding, which is considered as a partial defense mechanism against obesity. However, the molecular mechanism of diet-induced thermogenesis has remained unclear. Here we found that metallopeptidase nardilysin (NRDC) expression in liver is increased by fasting and decreased by re-feeding in wild-type mice. To elucidate the liver-specific role of NRDC in energy metabolism, we established hepatocyte-specific NRDC deficient mice (LKO). These mice showed intriguing phenotypes including 1) elevation of thermogenic genes in BAT, 2) decrease in lipid accumulation in BAT, and 3) increase in whole-body energy expenditure. These results suggested that the loss of NRDC in hepatocyte enhances adaptive thermogenesis in BAT by an inter-organ metabolic network. Notably, the phenotypic difference between control and LKO was completely eliminated by hepatic vagotomy or elevation of ambient temperature to thermoneutral range (30℃). Furthermore, LKO showed a significant increase in skin blood flow of the plantar at room temperature (23℃), suggesting that heat dissipation is enhanced in LKO. Taken together, these results indicate that hepatic NRDC regulates skin blood flow, thus heat dissipation via nervous system. BAT thermogenesis was then enhanced to compensate for the heat loss. In conclusion, NRDC, a novel sensor of nutrition, mediates diet-induced thermogenesis.