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

Abstract

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.In mammals, including humans, many aspects of behavior and physiology display daily oscillations. Twenty-four-hour rhythms of sleep, feeding behavior, core body temperature, hormone secretion, lipid and carbohydrate metabolism, and blood pressure are well-documented examples. These rhythms are driven by self-sustained endogenous clocks located in virtually all cells of the body and forming an integrated system (44, 48). The circadian (ϳ24-h) system is organized hierarchically with, at the top, a master clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus and oscillating with an approximately 24-h period in the absence of external time cues. Every day, this central clock is reset by light through the retinohypothalamic tract to keep the physiology synchronized to the external light/dark (LD) cycle. Circadian clocks present in the periphery are entrained by the SCN through internal synchronizers that have yet to be identified, and although they display self-sustained oscillations at the single-cell level, at the organ and systemic levels they require an intact SCN clock to remain in phase (63). Forward genetics and biochemical approaches have identified a set of core clock genes that interact through complex positive-and negative-feedback loops to form a molecular clock generating ϳ24-h oscillations (29). In this mechanism, the two bHLH-PAS transcriptional activators CLOCK (or N...

Differential coupling of KLF10 to Sin3-HDAC and PCAF regulates the inducibility of the FOXP3 gene

“…9). The trend to enhanced KLF10 expression upon mutation of the SID likely relates to the established capacity of wt KLF10 to repress its own gene transcription (18). After a 48-h resting period, cells were stimulated for 5 days to induce FOXP3 through TCR activation and exogenous TGF␤ (see MATERIALS AND METHODS).…”

Kruppel-like factor 4 is critical for transcriptional control of cardiac mitochondrial homeostasis

“…Since then, 8 additional members of this gene family have been shown to regulate adipogenesis both in mammals and worms (52,53). Several KLF factors (e.g., KLF10, KLF11, KLF15) have been shown to regulate hepatic metabolism (22,(54)(55)(56). KLF15 has also been shown to control lipid flux and metabolism in cardiac and skeletal muscles (57,58).…”

Deleted in Breast Cancer 1 (DBC1) Protein Regulates Hepatic Gluconeogenesis

“…PEPCK is regulated by several signaling systems, including the glucagon-cAMP and the insulin-AKT pathways (1). In addition, like many other metabolically relevant enzymes, PEPCK displays a circadian regulation (5). Central to the metabolic circadian rhythms are the nuclear receptors Rev-erbs (6).…”