Application of high glucose concentrations to fibroblast cell cultures leads to acute transcriptional repression of the Per1, Per2, and Bmal1 genes, thereby synchronizing fibroblast clocks ( Hirota et al., 2002). This is reminiscent of glucocorticoid or glucocorticoid analog synchronization of cell cultures ( Balsalobre et al., 2000), with the difference being that they induce Per1

and Per2 gene expression that leads to a repression www.selleckchem.com/products/cobimetinib-gdc-0973-rg7420.html of their own transcription and subsequent synchronization of all cells within hours. Glucose appears to upregulate TIEG1 (KLF10), a negatively acting zinc-finger transcription factor ( Hirota et al., 2002). It binds to two GC-rich elements in the Bmal1 promoter and thereby represses Bmal1 transcription. In vitro experiments have shown that siRNA-mediated knockdown of TIEG1/KLF10 causes

period shortening of cellular bioluminescence rhythms driven by Bmal1-luciferase and Per2-luciferase reporters ( Hirota et al., 2010a). Interestingly, Tieg1/Klf10 is regulated by BMAL1/CLOCK and thus appears to be part of a feedback loop involving the circadian clock and glucose levels ( Guillaumond click here et al., 2010) ( Figure 4). Accordingly, glucose absorbed with food or generated by gluconeogenesis will stimulate Tieg1/Klf10 expression and reduce the expression of Bmal1 and genes encoding for enzymes involved in gluconeogenesis. In line with this notion is the observation that Klf10 knockout mice display postprandial and fasting hyperglycemia, although curiously, this has only been observed in male mice. However, KLF10 is implicated in circadian lipid and cholesterol homeostasis in females ( Guillaumond et al., 2010). Collectively, it appears that TIEG1/KLF10 is a transcriptional regulator that links the circadian clock to energy metabolism in the liver. One measure of metabolic state is the ratio between AMP and ATP. Once the ratio increases EPHB3 (high AMP levels), cells reduce the

activity of ATP-consuming pathways and increase the activity of ATP-generating pathways. A major sensor for the AMP/ATP ratio is adenosine monophosphate-dependent protein kinase (AMPK), which becomes activated when AMP binds to its γ-subunit. This binding elicits a structural change in the AMPK catalytic α-subunit, making it a substrate for liver kinase B1 (LKB1). LKB1 then phosphorylates a threonine in the α-subunit of AMPK, leading to activation of AMPK (Carling et al., 2011). It appears that AMPK impacts circadian clock mechanisms in various ways. It can directly phosphorylate CRY1, leading to destabilization and degradation of this core clock protein (Lamia et al., 2009) and consequently affecting the negative limb of the circadian clock mechanism (Figure 4). The activity of AMPK kinase also appears to modulate PER2 protein stability via an indirect mechanism involving casein kinase 1ε (CK1ε).