Hepsin enhances liver metabolism and inhibits adipocyte browning in mice

Significance Hepsin is a cell membrane-bound enzyme discovered in the human liver. To date, the function of hepsin in the body remains unclear. Here we show that hepsin increases glycogen and lipid production in the liver and lowers metabolic rates and adipose tissue browning in mice. This function is medicated by the activation of hepatocyte growth factor and downstream Met signaling in both hepatocytes and adipocytes. Hepsin-deficient mice are resistant to obesity, hyperglycemia, and hyperlipidemia caused by a high-fat diet or leptin receptor deficiency. Our findings identify hepsin as a key regulator in the liver and energy metabolism, suggesting that hepsin may be a novel therapeutic target for obesity, dyslipidemia, and diabetes.