Protection against diet-induced obesity and obesity- related insulin resistance in Group 1B PLA2-deficient mice

Center for Lipid and Arteriosclerosis Studies, Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267 Group 1B phospholipase A 2 (PLA 2 ) is an abundant lipolytic enzyme that is well characterized biochemically and structurally. Because of its high level of expression in the pancreas, it has been presumed that PLA 2 plays a role in the digestion of dietary lipids, but in vivo data have been lacking to support this theory. Our initial study on mice lacking PLA 2 demonstrated no abnormalities in dietary lipid absorption in mice consuming a chow diet. However, the effects of PLA 2 deficiency on animals consuming a high-fat diet have not been studied. To investigate this, PLA 2 +/+ and PLA 2 / mice were fed a western diet for 16 wk. The results showed that PLA 2 / mice were resistant to high-fat diet-induced obesity. This observed weight difference was due to decreased adiposity present in the PLA 2 / mice. Compared with PLA 2 +/+ mice, the PLA 2 / mice had 60% lower plasma insulin and 72% lower plasma leptin levels after high-fat diet feeding. The PLA 2 / mice also did not exhibit impaired glucose tolerance associated with the development of obesity-related insulin resistance as observed in the PLA 2 +/+ mice. To investigate the mechanism by which PLA 2 / mice exhibit decreased weight gain while on a high-fat diet, fat absorption studies were performed. The PLA 2 / mice displayed 50 and 35% decreased plasma [ 3 H]triglyceride concentrations 4 and 6 h, respectively, after feeding on a lipid-rich meal containing [ 3 H]triolein. The PLA 2 / mice also displayed increased lipid content in the stool, thus indicating decreased fat absorption in these animals. These results suggest a novel role for PLA 2 in the protection against diet-induced obesity and obesity-related insulin resistance, thereby offering a new target for treatment of obesity and diabetes. phospholipase A 2 ; lipase; pancreatic enzymes; animal models; lipid absorption