title: Overexpression of peroxisome proliferator-activated receptor α in pancreatic β-cells improves glucose tolerance in diet-induced obese mice.
abstract: 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.
authors.affiliation: Northern Medical Program, University of Northern British Columbia, Prince George, BC, Canada. sgray0@unbc.ca
authors.forename: K-Lynn N
authors.initials: KL
authors.lastname: Hogh
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Uy
authors.forename: Ali
authors.initials: A
authors.lastname: Asadi
authors.forename: Robert K
authors.initials: RK
authors.lastname: Baker
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Riedel
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gray
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D000229:Dependovirus / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D007328:Insulin; D047493:PPAR alpha