Open AccessKrüppel-Like Factor KLF10 Is a Link between the Circadian Clock and Metabolism in Liver
Author(s) -
Fabienne Guillaumond,
Aline Gréchez-Cassiau,
Malayannan Subramaniam,
Sophie Brangolo,
Brigitta Peteri-Brunbäck,
Bart Staels,
Catherine Fiévet,
Thomas C. Spelsberg,
Franck Delaunay,
Michèle Teboul
Publication year - 2010
Publication title -
molecular and cellular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.14
H-Index - 327
eISSN - 1067-8824
pISSN - 0270-7306
DOI - 10.1128/mcb.01141-09
Subject(s) - biology , circadian rhythm , circadian clock , clock , transcriptome , postprandial , knockout mouse , molecular clock , microbiology and biotechnology , endocrinology , lipid metabolism , downregulation and upregulation , regulation of gene expression , gene , medicine , gene expression , genetics , insulin , phylogenetics
The circadian timing system coordinates many aspects of mammalian physiology and behavior in synchrony with the external light/dark cycle. These rhythms are driven by endogenous molecular clocks present in most body cells. Many clock outputs are transcriptional regulators, suggesting that clock genes primarily control physiology through indirect pathways. Here, we show that Krüppel-like factor 10 (KLF10) displays a robust circadian expression pattern in wild-type mouse liver but not in clock-deficient Bmal1 knockout mice. Consistently, the Klf10 promoter recruited the BMAL1 core clock protein and was transactivated by the CLOCK-BMAL1 heterodimer through a conserved E-box response element. Profiling the liver transcriptome from Klf10(-/-) mice identified 158 regulated genes with significant enrichment for transcripts involved in lipid and carbohydrate metabolism. Importantly, approximately 56% of these metabolic genes are clock controlled. Male Klf10(-/-) mice displayed postprandial and fasting hyperglycemia, a phenotype accompanied by a significant time-of-day-dependent upregulation of the gluconeogenic gene Pepck and increased hepatic glucose production. Consistently, functional data showed that the proximal Pepck promoter is repressed directly by KLF10. Klf10(-/-) females were normoglycemic but displayed higher plasma triglycerides. Correspondingly, rhythmic gene expression of components of the lipogenic pathway, including Srebp1c, Fas, and Elovl6, was altered in females. Collectively, these data establish KLF10 as a required circadian transcriptional regulator that links the molecular clock to energy metabolism in the liver.