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

• Published in: Experimental physiology Vol. 98; no. 2; pp. 564 - 575
• 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, UK Blackwell Publishing Ltd 01.02.2013
• Subjects: Animals; Blood Glucose - metabolism; Cell Line, Tumor; Dependovirus - genetics; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diabetes Mellitus, Type 2 - prevention & control; Diet, High-Fat; Disease Models, Animal; Disease Progression; Genetic Therapy - methods; Genetic Vectors; Insulin - blood; Insulin Resistance; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Obesity - blood; Obesity - etiology; Obesity - genetics; Obesity - physiopathology; Obesity - therapy; Phenotype; PPAR alpha - genetics; PPAR alpha - metabolism; Time Factors; Transfection; Up-Regulation
• 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 α (PPARα) specifically in pancreatic β‐cells of diet‐induced obese mice preserve pancreatic β‐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 β‐cell‐specific PPARα overexpression in a murine model of diet‐induced obesity. We show that pancreatic β‐cell‐specific overexpression of PPARα significantly improves glucose tolerance in diet‐induced obese mice. These results suggest that activation of β‐cell PPARα may be an appropriate target to preserve β‐cell function in obesity‐induced diabetes. Lipotoxicity is implicated in pancreatic β‐cell dysfunction in obesity‐induced type 2 diabetes. In vitro, activation of peroxisome proliferator‐activated receptor α (PPARα) has been shown to protect pancreatic β‐cells from the lipotoxic effects of palmitate, thereby preserving insulin secretion. Utilizing an adeno‐associated virus (dsAAV8), overexpression of PPARα was induced specifically in pancreatic β‐cells of adult, C57Bl/6 mice fed a high‐fat diet for 20 weeks and carbohydrate metabolism and β‐cell mass assessed. We show that overexpression of PPARα in pancreatic β‐cells in vivo preserves β‐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 β‐cell mass were observed in PPARα‐overexpressing mice compared with diet‐induced obese control animals. This model of β‐cell‐specific PPARα overexpression provides a useful in vivo model for elucidating the mechanisms underlying β‐cell lipotoxicity in obesity‐induced type 2 diabetes.