title: The clock gene Rev-erbα regulates pancreatic β-cell function: modulation by leptin and high-fat diet.
abstract: Disturbances of circadian rhythms have been associated with obesity and type 2 diabetes. The nuclear receptor Rev-erbα was suggested to link circadian rhythms and metabolism in peripheral tissues. The aim of the present study was to dissect the role of this clock gene in the pancreatic β-cell function and to analyze whether its expression is modulated by leptin and diet-induced obesity. To address the function of Rev-erbα, we used small interfering RNA in mouse islet cells and in MIN-6 cells. Cell proliferation was measured by bromodeoxyuridine incorporation, apoptosis by the terminal deoxynucleotidyl transferase dUTP nick end labeling technique, insulin secretion by RIA, and gene expression by RT-PCR. Pancreatic islets were isolated at different zeitgeber times 0, 6, and 12 after 6 wk of high-fat diet treatment, and then gene expression and insulin secretion were determined. Rev-erbα down-regulation by small interfering RNA treatment in islet cells and MIN-6 cells impaired glucose-induced insulin secretion, decreased the expression of key lipogenic genes, and inhibited β-cell proliferation. In vivo and in vitro leptin treatment increased Rev-erbα expression in isolated islets through a MAPK pathway. High-fat diet treatment disrupted the circadian Rev-erbα gene expression profile along with insulin secretion, indicating an important role of this clock gene in β-cell function. These results indicate that the clock gene Rev-erbα plays multiple functions in the pancreatic β-cell. Although the increase in Rev-erbα expression may promote β-cell adaptation in different metabolic situations, its deregulation may lead to altered β-cell function.
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernandez, Avenida de la Universidad s/n, 03202 Elche, Spain.
authors.forename: Elaine
authors.initials: E
authors.lastname: Vieira
authors.forename: Laura
authors.initials: L
authors.lastname: Marroquí
authors.forename: Thiago M
authors.initials: TM
authors.lastname: Batista
authors.forename: Ernesto
authors.initials: E
authors.lastname: Caballero-Garrido
authors.forename: Everardo M
authors.initials: EM
authors.lastname: Carneiro
authors.forename: Antonio C
authors.initials: AC
authors.lastname: Boschero
authors.forename: Angel
authors.initials: A
authors.lastname: Nadal
authors.forename: Ivan
authors.initials: I
authors.lastname: Quesada
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002940:Circadian Rhythm; D004032:Diet / Q000009:adverse effects*; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D020738:Leptin / Q000097:blood / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D004041:Dietary Fats; D007328:Insulin; D020738:Leptin; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D020929:Mitogen-Activated Protein Kinase Kinases