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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
Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
Northern Medical Program, University of Northern British Columbia, Prince George BC, Canada.
VTT Technical Research Centre of Finland, Espoo, Finland; Steno Diabetes Center A/S, Gentofte, Denmark.
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2014 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, no 10, p. 3843-3852Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press, 2014. Vol. 155, no 10, p. 3843-3852
National Category
Endocrinology and Diabetes Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:oru:diva-63696DOI: 10.1210/en.2014-1076ISI: 000342345000013PubMedID: 25051434Scopus ID: 2-s2.0-84907200623OAI: oai:DiVA.org:oru-63696DiVA, id: diva2:1169261
Funder
EU, FP7, Seventh Framework Programme, Project BetaBat 277713
Note

Funding agencies:

Canadian Diabetes Association  University of Northern British Columbia Research Project Awards  

Available from: 2017-12-22 Created: 2017-12-22 Last updated: 2018-01-29Bibliographically approved

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Oresic, Matej

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