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 language | English |
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Pages (from-to) | 3843-3852 |
Number of pages | 9 |
Journal | Endocrinology |
Volume | 155 |
Issue number | 10 |
DOIs | |
Publication status | Published - 2014 |
MoE publication type | A1 Journal article-refereed |