The Clock GeneRev-erbα Regulates Pancreatic β-Cell Function: Modulation by Leptin and High-Fat Diet

Dec 15, 2011Endocrinology

The body clock gene Rev-erbα controls insulin-producing cell function and is influenced by leptin and a high-fat diet

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Abstract

Down-regulation of Rev-erbα in pancreatic islet cells impaired glucose-induced insulin secretion and decreased the expression of key lipogenic genes.

Rev-erbα is linked to pancreatic β-cell function and metabolism.
Leptin treatment increased Rev-erbα expression in isolated islets via a MAPK pathway.
High-fat diet treatment disrupted the normal circadian expression profile of Rev-erbα.
Impaired Rev-erbα function is associated with decreased β-cell proliferation.
Altered Rev-erbα regulation may affect insulin secretion in metabolic conditions.

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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.

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The Clock GeneRev-erbα Regulates Pancreatic β-Cell Function: Modulation by Leptin and High-Fat Diet

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