1. Overexpression of PPARγ specifically in pancreatic β-cells exacerbates obesity-induced glucose intolerance, reduces β-cell mass, and alters islet lipid metabolism in male mice
- Author
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Matej Orešič, Sarah L. Gray, Ali Asadi, Michael N. Craig, Christopher E. Uy, Robert K. Baker, K-Lynn N. Hogh, Alexander P. Rudecki, Jordie D. Fraser, Madeline Speck, and Heli Nygren
- Subjects
Male ,medicine.medical_specialty ,Ceramide ,Transgene ,Cell- och molekylärbiologi ,Peroxisome proliferator-activated receptor ,Cell Count ,Mice, Transgenic ,Biology ,Carbohydrate metabolism ,Endocrinology and Diabetes ,chemistry.chemical_compound ,Islets of Langerhans ,Mice ,Endocrinology ,SDG 3 - Good Health and Well-being ,Internal medicine ,Insulin-Secreting Cells ,Genetic model ,Glucose Intolerance ,medicine ,Animals ,Obesity ,Receptor ,Cells, Cultured ,chemistry.chemical_classification ,geography ,geography.geographical_feature_category ,Lipid metabolism ,Islet ,Lipid Metabolism ,Up-Regulation ,Mice, Inbred C57BL ,PPAR gamma ,chemistry ,Organ Specificity ,Endokrinologi och diabetes ,Carbohydrate Metabolism ,Cell and Molecular Biology - Abstract
The contribution of peroxisomal proliferator-activated receptor (PPAR)-γ agonism in pancreatic β-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic β-cell PPARγ ablation have revealed a potential role for PPARγ in β-cell expansion in obesity but a limited role in normal β-cell physiology. Here we overexpressed PPARγ1 or PPARγ2 specifically in pancreatic β-cells of mice subjected to high-fat feeding using an associated adenovirus (β-PPARγ1-HFD and β-PPARγ2-HFD mice). We show β-cell-specific PPARγ1 or PPARγ2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased β-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice (β-eGFP-HFD mice). Analysis of islet lipid composition in β-PPARγ2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly β-PPARγ2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in β-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and β-oxidation. In summary, transgenic overexpression of PPARγ in β-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of β-oxidative genes, and reduced β-cell mass., Funding agencies:Canadian Diabetes Association University of Northern British Columbia Research Project Awards
- Published
- 2014
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