Increased fat mass and insulin resistance in mice lacking pancreatic lipase-related protein 1

Pancreatic triglyceride lipase (PTL) and its cofactor, colipase, are required for efficient dietary triglyceride digestion. In addition to PTL, pancreatic acinar cells synthesize two pancreatic lipase-related proteins (PLRP1 and PLRP2), which have a high degree of sequence and structural homology with PTL. The lipase activity of PLRP2 has been confirmed, whereas no known triglyceride lipase activity has been detected with PLRP1 up to now. To explore the biological functions of PLRP1 in vivo, we generated Plrp1 knockout (KO) mice in our laboratory. Here we show that the Plrp1 KO mice displayed mature-onset obesity with increased fat mass, impaired glucose clearance and the resultant insulin resistance. When fed on high-fat (HF) diet, the Plrp1 KO mice exhibited an increased weight gain, fat mass and severe insulin resistance compared with wild-type mice. Pancreatic juice extracted from Plrp1 KO mice had greater ability to hydrolyze triglyceride than that from the wild-type littermates. We propose that PLRP1 may function as a metabolic inhibitor in vivo of PLT-colipase-mediated dietary triglyceride digestion and provides potential anti-obesity targets for developing new drugs.