, 2009 and Ramsey et al., 2009). Disruption of NAD+ oscillation by mutations to NAD+ hydrolase CD38 alters behavioral and metabolic circadian rhythms (Sahar et al., 2011). Specifically, CD38-deficient mice display shortened circadian periodicity and alterations in plasma levels of amino acids. These data illustrate the importance of oscillating NAD+ levels and highlight its importance in amino acid regulation. Oscillating NAD+ levels also have indirect involvement in the regulation of brain function because several amino acids, such as tryptophan, tyrosine, glutamate, aspartate, glycine, and GABA, are either precursors of neurotransmitters or themselves neurotransmitters.

Volasertib concentration Although NAD+ is modulated by many additional processes (e.g., glycolysis, fatty acid synthesis), its regulation via NAMPT reinforces coupling between the circadian clock mechanism and NAD+-dependent metabolic pathways. In addition to the BMAL1/CLOCK and BMAL1/NPAS2 heterodimers that can serve as sensors for the

NAD(P)+/NAD(P)H ratio, the NAD+-dependent enzymes SIRT1 and PARP-1 may also link this metabolic ratio to the circadian clock. Levels of the enzyme SIRT1, which deacetylates histones and several transcription factors Bioactive Compound Library (Blander and Guarente, 2004), fluctuate throughout the day (Asher et al., 2008), and its activity may change as well (Nakahata et al., 2008). This enzyme physically interacts with BMAL1/CLOCK heterodimers, leading to a rhythmic deacetylation of BMAL1, histone H3 (Nakahata et al., 2008), and PER2 (Asher et al., 2008). As a result, the stability and/or activity of these proteins may be affected and lead to changes in circadian

gene expression. Interestingly, SIRT1 also affects the activity of other transcription factors such as PPARα (Purushotham et al., 2009) and coactivator PGC-1α (Rodgers et al., 2005), highlighting another avenue for the modulation of circadian gene expression and metabolism in the liver. Specifically, PGC-1α appears to be tightly linked to the circadian clock mechanism because it is expressed in a circadian fashion and serves as a coactivator of ROR (Liu et al., 2007), an activator of several clock components (see above and Figures 2 and 4). Furthermore, PGC-1α is a coactivator of FOXO1, which is part of a fasting-inducible switch that modulates gluconeogenesis (Liu et al., almost 2008). These relationships illustrate how circadian mechanisms and energy homeostasis could be related. Another potential NAD+ sensor is PARP-1 (Asher et al., 2010), a feeding-dependent factor implicated in the phase entrainment of peripheral oscillators. Illustrating a possible way to orchestrate feeding-induced phase changes and glucose homeostasis, PARP1 acts by binding to FOXO1 and attenuating the transactivation potential of the latter (Sakamaki et al., 2009). Several organic molecules serve as ligands for nuclear receptors, which regulate specific genes in response to ligand binding.