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

4 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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Glucose Intolerance
Insulin-Secreting Cells
Lipid Metabolism
Obesity
Obese Mice
Lipids
Insulin
Diet
Thiazolidinediones
Cell Physiological Phenomena
Lysophosphatidylcholines
Ceramides
Genetic Models
Carbohydrate Metabolism
Gene Expression Profiling
Islets of Langerhans
Hypoglycemic Agents
Adenoviridae
Genes
Triglycerides

Cite this

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. ; Oresic, Matej ; Gray, Sarah L. / 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. In: Endocrinology. 2014 ; Vol. 155, No. 10. pp. 3843-3852.
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title = "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",
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.",
author = "Hogh, {K-Lynn N.} and Craig, {Michael N.} and Uy, {Christopher E.} and Heli Nygren and Ali Asadi and Madeline Speck and Fraser, {Jordie D.} and Rudecki, {Alexander P.} and Baker, {Robert K.} and Matej Oresic and Gray, {Sarah L.}",
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doi = "10.1210/en.2014-1076",
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journal = "Endocrinology",
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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. / 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.; Oresic, Matej; Gray, Sarah L. (Corresponding Author).

In: Endocrinology, Vol. 155, No. 10, 2014, p. 3843-3852.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - 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

AU - Hogh, K-Lynn N.

AU - Craig, Michael N.

AU - Uy, Christopher E.

AU - Nygren, Heli

AU - Asadi, Ali

AU - Speck, Madeline

AU - Fraser, Jordie D.

AU - Rudecki, Alexander P.

AU - Baker, Robert K.

AU - Oresic, Matej

AU - Gray, Sarah L.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1210/en.2014-1076

DO - 10.1210/en.2014-1076

M3 - Article

VL - 155

SP - 3843

EP - 3852

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 10

ER -