Overexpression of peroxisome proliferator-activated receptor [alpha] in pancreatic [beta]-cells improves glucose tolerance in diet-induced obese mice

• Published in: Experimental physiology Vol. 98; no. 2; p. 564
• Main Authors: Hogh, K-Lynn N, Uy, Christopher E, Asadi, Ali, Baker, Robert K, Riedel, Michael J, Gray, Sarah L
• Format: Journal Article
• Language: English
• Published: Oxford John Wiley & Sons, Inc 01.02.2013
• ISSN: 0958-0670; 1469-445X
• DOI: 10.1113/expphysiol.2012.068734

New findings * What is the central question of this study?; Does overexpression of peroxisome proliferator-activated receptor [alpha] (PPAR[alpha]) specifically in pancreatic [beta]-cells of diet-induced obese mice preserve pancreatic [beta]-cell function and delay the onset of obesity-induced diabetes? * What is the main finding and its importance?; This study reports the phenotype of the first in vivo model of [beta]-cell-specific PPAR[alpha] overexpression in a murine model of diet-induced obesity. We show that pancreatic [beta]-cell-specific overexpression of PPAR[alpha] significantly improves glucose tolerance in diet-induced obese mice. These results suggest that activation of [beta]-cell PPAR[alpha] may be an appropriate target to preserve [beta]-cell function in obesity-induced diabetes. Lipotoxicity is implicated in pancreatic [beta]-cell dysfunction in obesity-induced type 2 diabetes. In vitro, activation of peroxisome proliferator-activated receptor [alpha] (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. [PUBLICATION ABSTRACT]