Characterization of PPAR-alpha overexpression in beta-cell lipotoxicity and its effects on obesity-induced type 2 diabetes.

Lipotoxicity is implicated as a mechanism for pancreatic β-cell dysfunction in obesity-induced type 2 diabetes (T2D). In vitro, peroxisome proliferator-activated receptor alpha (PPARα) protects against lipotoxic β-cell dysfunction preserving insulin secretion. Utilizing an adeno-associated virus (dsAAV8), we induced overexpression of PPARα specifically in pancreatic β-cells of adult, C57B16 mice that were fed a high-fat diet for 20 weeks to induce obesity. We show that overexpression of PPARα in pancreatic β-cells, in vivo, protects β-cell function in obesity, improving glucose tolerance by preserving insulin secretion compared to obese controls. No change in islet morphology or β-cell mass was observed. Despite metabolic improvements observed in diet-induced obese mice, overexpression of PPARα in pancreatic β-cells of a genetic model of severe obesity (db/db) did not improve carbohydrate metabolism. We have developed the first in vivo model of β-cell specific PPARα overexpression to elucidate the mechanisms involved in β-cell lipotoxicity in obesity-induced T2D.