Overexpression of peroxisome proliferator-activated receptor α in pancreatic β-cells improves glucose tolerance in diet-induced obese mice

Lipotoxicity is implicated in pancreatic beta-cell dysfunction in obesity-induced type 2 diabetes. In vitro, activation of peroxisome proliferator-activated receptor a (PPAR alpha) has been shown to protect pancreatic beta-cells from the lipotoxic effects of palmitate, thereby preserving insulin secretion. Utilizing an adeno-associated virus (dsAAV8), overexpression of PPAR alpha was induced specifically in pancreatic beta-cells of adult, C57Bl/6 mice fed a high-fat diet for 20 weeks and carbohydrate metabolism and beta-cell mass assessed. We show that overexpression of PPAR alpha in pancreatic beta-cells in vivo preserves beta-cell function in obesity, and this improves glucose tolerance by preserving insulin secretion in comparison to control mice with diet-induced obesity. No changes in beta-cell mass were observed in PPAR alpha-overexpressing mice compared with diet-induced obese control animals. This model of beta-cell-specific PPAR alpha overexpression provides a useful in vivo model for elucidating the mechanisms underlying beta-cell lipotoxicity in obesity-induced type 2 diabetes.