Of the 49 nuclear receptors, 20 have been reported to display a c

Of the 49 nuclear receptors, 20 have been reported to display a circadian pattern of mRNA expression in the liver, 19

in white adipose tissue, 18 in brown adipose tissue, and seven in muscle (Yang et al., 2006). The receptors that display these circadian patterns include various isoforms of PPAR, REV-ERB, ROR, and TR. Some of these receptors, such as the REV-ERBs and the RORs, are directly involved in the modulation of the core clock circuitry (Figure 2) and may interact with clock components including PER2 (Schmutz et al., 2010) and CRY (Lamia et al., 2011). Other nuclear receptors, including LXR and FXR, can LDK378 either stimulate or repress genes that produce molecular ligands; one example is the regulation of Cyp7a1. This gene encodes for the rate-limiting enzyme that converts cholesterol to bile acids ( Peet et al., 1998), possibly affecting the intracellular levels of sterol compounds that suppress the transactivational activities of the core clock factors RORα and RORγ in the liver. Fatty acids and their intermediates are natural ligands for PPARs. PPARs regulate adipocytes and insulin sensitivity (PPARγ), modulate the fatty acid oxidation system in mitochondria (PPARα), and regulate cell proliferation, differentiation, and migration in wound healing and inflammatory processes (PPARδ). The isoforms PPARα and PPARγ

find more have been shown to interact (directly or indirectly) with PER2 (Grimaldi et al., 2010 and Schmutz et al., 2010), leading to a time-of-day-dependent modulation

of lipid metabolism (Figure 4) (Grimaldi et al., 2010). In addition, PER3 appears to form a complex with PPARγ, leading to reduced transactivation potential of this nuclear receptor. Accordingly, an increase in adipose tissue and a decrease in muscle tissue were observed in Per3-deficient mice ( Costa et al., 2011). Interestingly, PER2 appears to regulate gamma interferon production in natural killer cells ( Liu et al., 2006), pointing to a potential modulatory function of PER2 for PPARδ. Regulation of glucose homeostasis involves Mephenoxalone glucocorticoids and its receptor. A recent study reported that the clock components of the cryptochrome (Cry) family interact with GR and modulate glucose homeostasis ( Figure 4) ( Lamia et al., 2011). This interaction reduces GR activation potential for the expression of the phosphoenolpyruvate caboxykinase 1 gene (Pck1)—a gene that encodes the rate-limiting enzyme in gluconeogenesis (PEPCK). Accordingly, Cry-deficient cells increased Pck1 expression in response to dexamethason (a synthetic glucocorticoid). In contrast the NF-κB signaling pathway, through which glucocorticoids modulate inflammation, was not affected. This indicates a separation of CRY function in the gluconeogenic and inflammatory pathways of glucocorticoid action ( Lamia et al., 2011). Therefore, modulation of CRY levels may be a potential therapeutic strategy to reduce the side-effects of glucocorticoids on metabolism (i.e.

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