Institute of Neurobiology, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany
Lisbeth Harder
Institute of Neurobiology, Center of Brain Behavior & Metabolism, University of Lübeck, Lübeck, Germany; Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden
José Thalles Lacerda
Department of Physiology, Institute of Bioscience, University of Sāo Paulo, Sāo Paulo, Brazil
Rex Parsons
Australian Centre for Health Services Innovation and Centre for Healthcare Transformation, School of Public Health and Social Work, Faculty of Health, Queensland University of Technology, Kelvin Grove, Australia
Meike Kaehler
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
Ingolf Cascorbi
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
Inga Nagel
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
Oliver Rawashdeh
School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, Australia
Jens Mittag
Center of Brain Behavior & Metabolism, Institute for Endocrinology and Diabetes – Molecular Endocrinology, University of Lübeck, Lübeck, Germany
Diurnal (i.e., 24 hr) 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. A 24-hr 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 (1033 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 summary, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.
