Nardilysin in hepatocyte regulates diet-induced thermogenesis via the modulation of brown adipose tissue activity

Abstract

Brown adipose tissue (BAT) is a major organ responsible for diet-induced thermogenesis, a phenomenon which converts excess energy intake into heat. Previous studies suggested that hepatocytes regulate diet-induced thermogenesis in response to changes in nutritional status. However, it is not clear how hepatocytes are involved in diet-induced thermogenesis.

Here, we demonstrate that liver nardilysin (NRDC) expression changes by nutritional state; it increases by fasting and decreases by re-feeding. Moreover, liver NRDC decreases upon high-fat diet (HFD) feeding. We have previously demonstrated that mice systemically deficient in a metallopeptidase nardilysin (NRDC) show reduced fat mass, enhanced energy expenditure and BAT activity. To clarify the liver-specific role of NRDC in diet-induced thermogenesis and energy metabolism, we established hepatocyte-specific Nrdc deficient mice (LKO). In HFD-fed state, the body weight gain was significantly suppressed, while glucose tolerance and insulin sensitivity were significantly improved in LKO. Measurement in metabolic cage demonstrated unchanged food intake and physical activity, while increased oxygen consumption rate and heat generation in LKO. BAT in LKO showed less fat accumulation and increased thermogenic genes such as UCP1 and PGC1a. Together, these results suggest that hepatic NRDC regulates diet-induced thermogenesis via BAT activity.