Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation

Abstract

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 - 15% of the liver transcriptome as rhythmic in control and T3 groups, but only 4% of the liver transcriptome (1,033 genes) were rhythmic across both conditions - amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice

“…For mesor and amplitude comparison, CircaCompare was allowed to fit a sine curve irrespective of rhythmicity thresholds. Phase comparison was only performed in robustly rhythmic genes as described (2).…”

“…1a; Table S1). Considering the marked rhythmicity of the liver transcriptome and liver metabolism (11,33) one explanation for this lack of consistency would be differences in sampling times and control thereof between studies.…”

The role of the circadian clock in the development, progression, and treatment of non‐alcoholic fatty liver disease

“…As one example, we recently showed that alterations in thyroid hormone state leads to a rewiring of the circadian liver transcriptome in mice. 14 Besides transcriptional control, clock proteins have been shown to interact with many other proteins. 15 These post-transcriptional hands provide further levels of complexity to the circadian regulation of physiology.…”

“…8,9 Circadian profiling of mouse livers showed that 10% or more of the transcriptome is rhythmically expressed. 14,21 It should be mentioned that the percentage of rhythmic genes varies widely between different studies depending on several factors such as sequencing method, temporal sample resolution, and algorithms to assess rhythmicity. The concordance between rhythmic genes and proteins is not linear and often both rhythms are not overlapping, suggesting that post-transcriptional and -translational modifications are important players in the generation of physiological rhythms.…”

“…[22][23][24] Specific gene programs for carbohydrate, lipid, amino acid, bile acid, and xenobiotic metabolism show a clear circadian profile, which may be affected in pathological conditions such as obesity or endocrine dysfunction. 14,25 Bmal1 deletion in the liver results in loss of rhythmicity in Glut2, which contributes to reduced glycogen, hypoglycemia, and hypoinsulinemia. 12 Interestingly, mice with liver specific knockout for Rorg are protected against insulin resistance, hyperglycemia, and steatosis.…”