Overexpression of PPAR{\gamma} Specifically in Pancreatic {\beta}-Cells Exacerbates Obesity-Induced Glucose Intolerance, Reduces {\beta}-Cell Mass, and Alters Islet Lipid Metabolism in Male Mice

The contribution of peroxisomal proliferator-activated receptor (PPAR)-{\gamma} agonism in pancreatic {\beta}-cells to the antidiabetic actions of thiazolidinediones has not been clearly elucidated. Genetic models of pancreatic {\beta}-cell PPAR{\gamma} ablation have revealed a potential role for PPAR{\gamma} in {\beta}-cell expansion in obesity but a limited role in normal {\beta}-cell physiology. Here we overexpressed PPAR{\gamma}1 or PPAR{\gamma}2 specifically in pancreatic {\beta}-cells of mice subjected to high-fat feeding using an associated adenovirus ({\beta}-PPAR{\gamma}1-HFD and {\beta}-PPAR{\gamma}2-HFD mice). We show {\beta}-cell-specific PPAR{\gamma}1 or PPAR{\gamma}2 overexpression in diet-induced obese mice exacerbated obesity-induced glucose intolerance with decreased {\gamma}-cell mass, increased islet cell apoptosis, and decreased plasma insulin compared with obese control mice ({\beta}-eGFP-HFD mice). Analysis of islet lipid composition in {\beta}-PPAR{\gamma}2-HFD mice revealed no significant changes in islet triglyceride content and an increase in only one of eight ceramide species measured. Interestingly {\beta}-PPAR{\gamma}2-HFD islets had significantly lower levels of lysophosphatidylcholines, lipid species shown to enhance insulin secretion in {\gamma}-cells. Gene expression profiling revealed increased expression of uncoupling protein 2 and genes involved in fatty acid transport and {\beta}-oxidation. In summary, transgenic overexpression of PPAR{\gamma} in {\beta}-cells in diet-induced obesity negatively impacts whole-animal carbohydrate metabolism associated with altered islet lipid content, increased expression of {\beta}-oxidative genes, and reduced {\beta}-cell mass.