Pancreatic acinar cell-specific overexpression of group 1B phospholipase A₂ exacerbates diet-induced obesity and insulin resistance in mice

Abstract

Genome-wide association studies have identified significant association between polymorphisms of the Group 1B phospholipase A₂ (PLA2G1B) gene and central obesity in humans. Previous studies have shown that Pla2g1b inactivation decreases post-prandial lysophospholipid absorption, and as a consequence increases hepatic fatty acid oxidation and protects against diet-induced obesity and glucose intolerance in mice. The present study showed that transgenic mice with pancreatic acinar cell-specific overexpression of the human PLA2G1B gene gained significantly more weight and displayed elevated insulin resistance characteristics, such as impaired glucose tolerance, compared with wild-type (WT) mice, when challenged with a high-fat/carbohydrate diet. Pre- and post-prandial plasma β-hydroxybutyrate levels were also lower, indicative of decreased hepatic fatty acid oxidation, in the hypercaloric diet-fed PLA2G1B transgenic mice. These, along with earlier observations of Pla2g1b-null mice, document that Pla2g1b expression level is an important determinant of susceptibility to diet-induced obesity and diabetes, suggesting that the relationship between PLA2G1B polymorphisms and obesity may be due to differences in PLA2G1B expression levels between these individuals. The ability of pancreas-specific overexpression of PLA2G1B to promote obesity and glucose intolerance suggests that target phospholipase activity in the digestive tract with non-absorbable inhibitors should be considered as a therapeutic option for metabolic disease therapy.