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

• Published in: Endocrinology (Philadelphia) Vol. 155; no. 10; pp. 3843 - 3852
• Main Authors: Hogh, K-Lynn N, Craig, Michael N, Uy, Christopher E, Nygren, Heli, Asadi, Ali, Speck, Madeline, Fraser, Jordie D, Rudecki, Alexander P, Baker, Robert K, Orešič, Matej, Gray, Sarah L
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.10.2014
• Subjects: Animals; Carbohydrate Metabolism - genetics; Cell Count; Cells, Cultured; Glucose Intolerance - genetics; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Islets of Langerhans - metabolism; Lipid Metabolism - genetics; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Obesity - complications; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Organ Specificity - genetics; PPAR gamma - genetics; PPAR gamma - metabolism; Up-Regulation - genetics
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2014-1076

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.