Novel role of Group 1B phospholipase A₂ in diet-induced obesity and insulin resistance:

The Group 1B phospholipase A₂ (PLA₂1B) is synthesized primarily in pancreatic acinar cells and has generally been thought to act only as a lipolytic enzyme, facilitating dietary lipid digestion and absorption in the gastrointestinal tract. However, our recent work showed that PLA₂1B is also synthesized in islet β-cells. Deletion of the PLA₂1B gene in mice resulted in animals that are more insulin sensitive and are resistant to diet-induced diabetes and obesity. Based on these observations, our current working hypothesis is that PLA₂1B synthesized by islet β-cells serves as a negative regulator of insulin-stimulated glucose uptake by liver, muscle, and adipose tissues. We further postulate that this PLA₂1B function is independent of the phospholipid hydrolytic activity of PLA₂1B, but rather related to alteration of insulin signaling mechanisms as a consequence of PLA₂1B interaction with PLA₂1B receptors on the surface of liver, muscle, and adipocytes. In contrast, the pancreatic acinar-cell derived PLA₂1B acts as a digestive enzyme in the intestinal lumen and this function is dependent on its enzymatic activity against phospholipids. Current projects in this area include:

1) Generating pancreatic acinar-specific PLA₂1B transgenic mice in PLA₂1B knockout background to test the hypothesis that the acinar-derived PLA₂1B functions only in modulation of dietary lipid absorption and is not involved in regulation of glucose tolerance, insulin sensitivity, and diet-induced diabetes and obesity. 

2) Islet transplants will be performed to test the hypothesis that genetic modification to decrease islet PLA₂1B gene expression is a viable strategy to increase glucose tolerance and insulin sensitivity, and prevent diet-induced insulin resistance and obesity in mice. 

3) Recombinant adenovirus encoding a soluble form of the PLA₂ receptor will be injected into C57BL/6 mice to block PLA₂1B binding to the PLA₂ receptor to test the hypothesis that PLA₂1B regulation of glucose tolerance and insulin sensitivity and diet-induced insulin resistance and obesity is dependent on its interaction with cell surface receptors. 

Collectively, these studies will define the multiple functions of PLA₂1B in physiology and pathophysiology.  This information will be valuable with the potential of offering novel strategy for treatment of insulin resistance, diabetes, and obesity.