Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. We explored these genes and created an expression panel that assesses liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH action under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state.

Circadian clocks regulate physiological functions, including energy metabolism, along the 24-hour day cycle. The mammalian clock system is organized in a hierarchical manner with a coordinating pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). The SCN clock is reset primarily by the external light-dark cycle while other zeitgebers such as the timing of food intake are potent synchronizers of many peripheral tissue clocks. Under conflicting zeitgeber conditions, e.g. during shift work, phase synchrony across the clock network is disrupted promoting the development of metabolic disorders. We established a zeitgeber desynchrony (ZD) paradigm to quantify the differential contributions of the two main zeitgebers, light and food, to the resetting of specific tissue clocks and the effect on metabolic homeostasis in mice. Under 28-hour light-dark and 24-hour feeding-fasting conditions SCN and peripheral clock, as well as activity and hormonal rhythms showed specific periodicities aligning in-between those of the two zeitgebers. During ZD, metabolic homeostasis was cyclic with mice gaining weight under synchronous and losing weight under conflicting zeitgeber conditions. In summary, our study establishes an experimental paradigm to compare zeitgeber input in vivo and study the physiological consequences of chronodisruption.