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

K-Lynn N. Hogh, Michael N. Craig, Christopher E. Uy, Heli Nygren, Ali Asadi, Madeline Speck, Jordie D. Fraser, Alexander P. Rudecki, Robert K. Baker, Matej Oresic, Sarah L. Gray (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

6 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)3843-3852
Number of pages9
JournalEndocrinology
Volume155
Issue number10
DOIs
Publication statusPublished - 2014
MoE publication typeA1 Journal article-refereed

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