Brown adipose tissue (BAT) plays a critical role in diet-induced thermogenesis, a process by which excess energy intake is consumed as heat. Several studies have suggested that hepatocytes regulate diet-induced thermogenesis in response to changes in nutritional status. However, the precise mechanisms by which hepatocytes contribute to this process are not yet fully understood.
We have previously demonstrated that mice systemically deficient in nardilysin (NRDC), a member of the M16 family of metalloendopeptidase, exhibit decreased adiposity, enhanced energy expenditure and BAT activity. To clarify the tissue-specific role of NRDC, we generated multiple lines of tissue-specific NRDC knockout mice. Among them, to our surprise, hepatocyte-specific NRDC knockout mice (LKO) showed 1) increased mRNA expression of thermogenic genes in BAT, 2) less fat accumulation in BAT, 3) increase in whole-body energy expenditure. Mechanistically, the deletion of NRDC in the liver enhances BAT theremogenesis at least partly thorough changes in humoral factors. We also found that liver nardilysin (NRDC) expression is modulated by nutrient availability with upregulation during fasting and downregulation during re-feeding. Furthermore, liver NRDC levels decrease upon high-fat diet feeding.
Taken together, these findings suggest that NRDC functions as a potential nutrition sensor in the liver and regulates diet-induced thermogenesis.