Krüppel-Like Factor KLF10 Is a Link between the Circadian Clock and Metabolism in Liver

Apr 14, 2010Molecular and cellular biology

KLF10 connects the body’s internal clock to liver metabolism

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Abstract

Krüppel-like factor 10 (KLF10) shows a robust circadian expression pattern in wild-type mouse liver but is absent in clock-deficient mice.

KLF10 is regulated by the core clock protein BMAL1, indicating its role in circadian rhythms.
Profiling of Klf10(-/-) mouse liver revealed 158 genes related to lipid and carbohydrate metabolism that are significantly affected.
Approximately 56% of these metabolic genes are controlled by the circadian clock.
Male Klf10(-/-) mice exhibited postprandial and fasting hyperglycemia, linked to increased expression of the gluconeogenic gene Pepck.
In Klf10(-/-) females, higher plasma triglycerides were observed, with altered rhythmic expression of genes involved in fat synthesis.

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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.

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Krüppel-Like Factor KLF10 Is a Link between the Circadian Clock and Metabolism in Liver

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