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- Title
Nuclear PLCs affect insulin secretion by targeting PPARγ in pancreatic β cells.
- Authors
Fiume, Roberta; Ramazzotti, Giulia; Faenza, Irene; Piazzi, Manuela; Bavelloni, Alberto; Billi, Anna Maria; Cocco, Lucio
- Abstract
Type 2 diabetes is a heterogeneous disorder caused by concomitant impairment of insulin secretion by pancreatic β cells and of insulin action in peripheral target tissues. Studies with inhibitors and agonists established a role for PLC in the regulation of insulin secretion but did not distinguish between effects due to nuclear or cytoplasmic PLC signaling pathways that act in a distinct fashion. We report that in MIN6 β cells, PLCβ1 localized in both nucleus and cytoplasm, PLCδ4 in the nucleus, and PLCγ1 in the cytoplasm. By silencing each isoform, we observed that they all affected glucose-induced insulin release both at basal and high glucose concentrations. To elucidate the molecular basis of PLC regulation, we focused on peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor transcription factor that regulates genes critical to β-cell maintenance and functions. Silencing of PLCβ1 and PLCδ4 resulted in a decrease in the PPARγ mRNA level. By means of a PPARγ- promoter-luciferase assay, the decrease could be attributed to a PLC action on the PPARγ-promoter region. The effect was specifically observed on silencing of the nuclear and not the cytoplasmic PLC. These findings highlight a novel pathway by which nuclear PLCs affect insulin secretion and identify PPARγ as a novel molecular target of nuclear PLCs.
- Subjects
TYPE 2 diabetes; PANCREATIC secretions; INSULIN; PHOSPHOINOSITIDES; CYTOPLASM; MESSENGER RNA
- Publication
FASEB Journal, 2012, Vol 26, Issue 1, p203
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.11-186510