PPAR~ regulates insulin secretion in pancreatic ~-cells : evidence from an in-vivo mouse model of ~-cell specific PPAR~ overexpression

Onset of obesity-induced type 2 diabetes occurs when pancreatic ~-cells fail to meet the increased insulin demand caused by insulin resistance. Changes in adipose tissue function in obesity results in abnormal deposition of lipids in non-adipose tissues including pancreatic islets. Chronic exposure to fatty acid is lipotoxic to the ~-cells, blunting glucose-stimulated insulin secretion. Peroxisome proliferator activated receptor-~ (PPAR~) belongs to the family of PPAR nuclear transcription factors, key regulators of lipid metabolism. In pancreatic ~-cells PPAR~ has been shown to regulate genes involved in mitochondrial handling of fatty acids causing up regulation of genes involved in mitochondrial fatty acid oxidation. In addition to its role in lipid metabolism, an in-vivo model of ~-cell specific PPAR~ knockout demonstrated a role for PPAR~ in regulating the cellular machinery involved in secretion of insulin granules. Removal of PPAR~ from the ~-cell enhanced second phase insulin secretion due to disassembly of filamentous actin, allowing uninhibited insulin granule secretion. The goal of my project was to determine if the pro-oxidative potential of PPAR~ could protect pancreatic ~-cells from lipotoxicity induced by obesity or if PPAR~\u2019s role in insulin secretion would prevent beneficial effects on ~-cell function. Utilizing an adeno-associated virus (dsAAV8), we induced overexpression of PPAR~ specifically in pancreatic ~-cells of adult C57B16 mice fed a chow or high-fat diet. We observed that overexpression of PPAR~ in pancreatic ~-cells, significantly impairs glucose-stimulated insulin secretion in both lean and obese mice supporting a role for PPAR~ in the regulation of insulin secretory mechanisms. Characterization of filamentous actin, expression and activity of SNARE proteins in ~-cells overexpressing PPAR~ will help to elucidate the mechanism by which PPAR~ results insulin granule exocytosis.