title: Peroxisome proliferator-activated receptor-gamma regulates expression of PDX-1 and NKX6.1 in INS-1 cells.
abstract: In the 60% pancreatectomy (Px) rat model of beta-cell adaptation, normoglycemia is maintained by an initial week of beta-cell hyperplasia that ceases and is followed by enhanced beta-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 beta-cell nuclear peroxisome proliferator-activated receptor (PPAR)-gamma protein, along with a 2-fold increase in nuclear pancreatic duodenal homeobox (Pdx)-1 protein and a 1.4-fold increase in beta-cell nuclear Nkx6.1 immunostaining. As PPAR-gamma activation is known to both lower proliferation and have prodifferentiation effects in many tissues, we studied PPAR-gamma actions in INS-1 cells. A 3-day incubation with the PPAR-gamma agonist troglitazone reduced proliferation and increased Pdx-1 and Nkx6.1 immunostaining, along with glucokinase and GLUT2. Also, a 75% knockdown of PPAR-gamma 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-gamma 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-gamma signaling in the beta-cell adaptation following a 60% Px in rats.
authors.affiliation: Cross Cancer Institute, University of Alberta, Edmonton, Canada.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Moibi
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Gupta
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jetton
authors.forename: Mina
authors.initials: M
authors.lastname: Peshavaria
authors.forename: Ronak
authors.initials: R
authors.lastname: Desai
authors.forename: Jack L
authors.initials: JL
authors.lastname: Leahy
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D018613:Microscopy, Confocal; D047493:PPAR alpha / Q000235:genetics; D047495:PPAR gamma / Q000502:physiology*; D010180:Pancreatectomy; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; D007328:Insulin; C491328:Nkx6-1 protein, mouse; D047493:PPAR alpha; D047495:PPAR gamma; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D012313:RNA; D005947:Glucose