Non-rhythmic modulators of the circadian system: A new class of circadian modulators

The temporal organization of biological processes is critical for an organism's fitness and survival. An internal circadian clock network coordinates the alignment between the external and internal milieus via an array of systemic factors carrying temporal information such as core body temperature, autonomic activity, hormonal secretion, and behavioral functions. Collectively, these so called zeitgebers are characterized by strong temporal variations (i.e., high amplitudes). At the same time, target tissues show time windows of highest and lowest sensitivity to specific zeitgebers and, in this way, tissues can further modulate the effect of zeitgeber input in a process known as circadian gating. Such interplay between systemic signals and local circadian gating, however, suggests an additional level of temporal control—the resetting of target tissue rhythms in response to altered levels of tonic (i.e., non-rhythmic) signals. The recently identified tuning of liver transcriptome rhythms by thyroid hormones (THs) is one example of such regulation. THs show low-amplitude rhythms in the serum levels that are easily disrupted by altered thyroid states. At the same time, circadian rhythms in TH target tissues, such as liver, are markedly affected by alterations in TH state. Temporal regulation of TH target genes in other tissues suggests similar effects across the body. This chapter describes the rationale, experimental evidence, and potential consequences of this new level of circadian regulators.