title: 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.
abstract: 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.
authors: Northern Medical Program (K.N.H., M.N.C., C.E.U., J.D.F., A.P.R., S.L.G.), University of Northern British Columbia, Prince George, British Columbia, Canada V2N 4Z9; Department of Cellular and Physiological Sciences and Faculty of Medicine (A.A., R.K.B.), University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4; VTT Technical Research Centre of Finland (H.N., M.O.), Espoo FI-02044, Finland; Steno Diabetes Center A/S (H.N., M.O.), Gentofte, Denmark; and Child and Family Research Institute (M.S.), Vancouver, British Columbia, Canada V6T 1Z1.
authors: K-Lynn N
authors: KL
authors: Hogh
authors: Michael N
authors: MN
authors: Craig
authors: Christopher E
authors: CE
authors: Uy
authors: Heli
authors: H
authors: Nygren
authors: Ali
authors: A
authors: Asadi
authors: Madeline
authors: M
authors: Speck
authors: Jordie D
authors: JD
authors: Fraser
authors: Alexander P
authors: AP
authors: Rudecki
authors: Robert K
authors: RK
authors: Baker
authors: Matej
authors: M
authors: Orešič
authors: Sarah L
authors: SL
authors: Gray
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000235:genetics; D002452:Cell Count; D002478:Cells, Cultured; D018149:Glucose Intolerance / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology*; D007515:Islets of Langerhans / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D047495:PPAR gamma