Peroxisome Proliferator–Activated Receptor-γ Regulates Expression of PDX-1 and NKX6.1 in INS-1 Cells
- Jacob A. Moibi1,
- Dhananjay Gupta2,
- Thomas L. Jetton2,
- Mina Peshavaria2,
- Ronak Desai2 and
- Jack L. Leahy2
- 1Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
- 2Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Vermont, Burlington, Vermont
- Address correspondence and reprint requests to Dr. Jack Leahy, University of Vermont College of Medicine, Given Bldg. C331, Burlington, VT 05405. E-mail: jleahy{at}uvm.edu
Abstract
In the 60% pancreatectomy (Px) rat model of β-cell adaptation, normoglycemia is maintained by an initial week of β-cell hyperplasia that ceases and is followed by enhanced β-cell function. It is unknown how this complex series of events is regulated. We studied isolated islets and pancreas sections from 14-day post-Px versus sham-operated rats and observed a doubling of β-cell nuclear peroxisome proliferator–activated receptor (PPAR)-γ protein, along with a 2-fold increase in nuclear pancreatic duodenal homeobox (Pdx)-1 protein and a 1.4-fold increase in β-cell nuclear Nkx6.1 immunostaining. As PPAR-γ activation is known to both lower proliferation and have prodifferentiation effects in many tissues, we studied PPAR-γ actions in INS-1 cells. A 3-day incubation with the PPAR-γ agonist troglitazone reduced proliferation and increased Pdx-1 and Nkx6.1 immunostaining, along with glucokinase and GLUT2. Also, a 75% knockdown of PPAR-γ using RNA interference lowered the mRNA levels of Pdx-1, glucokinase, GLUT2, and proinsulin II by more than half. Our results show a dual effect of PPAR-γ in INS-1 cells: to curtail proliferation and promote maturation, the latter via enhanced expression of Pdx-1 and Nkx6.1. Additional studies are needed to determine whether there is a regulatory role for PPAR-γ signaling in the β-cell adaptation following a 60% Px in rats.
- Pdx, pancreatic duodenal homeobox
- PPAR, peroxisome proliferator–activated receptor
- Px, pancreatectomy
- RNAi, RNA interference
- siRNA, small interfering RNA
- UCP, uncoupling protein
Footnotes
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J.A.M. and D.G. contributed equally to this work.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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- Accepted October 10, 2006.
- Received July 10, 2006.
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