title: Peroxisome proliferator-activated receptor γ (PPARγ) and its target genes are downstream effectors of FoxO1 protein in islet β-cells: mechanism of β-cell compensation and failure.
abstract: The molecular mechanisms and signaling pathways that drive islet β-cell compensation and failure are not fully resolved. We have used in vitro and in vivo systems to show that FoxO1, an integrator of metabolic stimuli, inhibits PPARγ expression in β-cells, thus transcription of its target genes (Pdx1, glucose-dependent insulinotropic polypeptide (GIP) receptor, and pyruvate carboxylase) that are important regulators of β-cell function, survival, and compensation. FoxO1 inhibition of target gene transcription is normally relieved when upstream activation induces its translocation from the nucleus to the cytoplasm. Attesting to the central importance of this pathway, islet expression of PPARγ and its target genes was enhanced in nondiabetic insulin-resistant rats and markedly reduced with diabetes induction. Insight into the impaired PPARγ signaling with hyperglycemia was obtained with confocal microscopy of pancreas sections that showed an intense nuclear FoxO1 immunostaining pattern in the β-cells of diabetic rats in contrast to the nuclear and cytoplasmic FoxO1 in nondiabetic rats. These findings suggest a FoxO1/PPARγ-mediated network acting as a core component of β-cell adaptation to metabolic stress, with failure of this response from impaired FoxO1 activation causing or exacerbating diabetes.
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Dhananjay
authors.initials: D
authors.lastname: Gupta
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Averi A
authors.initials: AA
authors.lastname: Leahy
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Navjot
authors.initials: N
authors.lastname: Monga
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Mina
authors.initials: M
authors.lastname: Peshavaria
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Jetton
authors.affiliation: From the Division of Endocrinology, Diabetes, and Metabolism and the Department of Medicine, University of Vermont, Burlington, Vermont 05405. Electronic address: jleahy@uvm.edu.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Leahy
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D014158:Transcription, Genetic
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; C074639:Foxo1 protein, rat
keywords: Chromatin Immunoprecipitation (ChiP); Gene Expression; Immunofluorescence; Mouse Models; PDX1; Pancreatic Islets; Pyruvate Carboxylase; Signal Transduction