title: Nuclear PLCs affect insulin secretion by targeting PPARγ in pancreatic β cells.
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.
authors.affiliation: Department of Human Anatomy, University of Bologna, Bologna, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fiume
authors.forename: Giulia
authors.initials: G
authors.lastname: Ramazzotti
authors.forename: Irene
authors.initials: I
authors.lastname: Faenza
authors.forename: Manuela
authors.initials: M
authors.lastname: Piazzi
authors.forename: Alberto
authors.initials: A
authors.lastname: Bavelloni
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Billi
authors.forename: Lucio
authors.initials: L
authors.lastname: Cocco
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology; D003593:Cytoplasm / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D020868:Gene Silencing; D005947:Glucose / Q000493:pharmacokinetics; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D007340:Insulinoma; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D054799:Phospholipase C beta / Q000235:genetics / Q000378:metabolism*; D054803:Phospholipase C delta / Q000235:genetics / Q000378:metabolism*; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology
chemical_list: D007328:Insulin; D047495:PPAR gamma; D054799:Phospholipase C beta; D054803:Phospholipase C delta; C518034:Plcb1 protein, mouse; C518031:Plcd4 protein, mouse; D051966:Phospholipase C gamma; D005947:Glucose