bioRxiv (Cold Spring Harbor Laboratory), Feb 2, 2024
Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In ... more Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRB KO ) mice under normal chow conditions revealed a markedly modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri-and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosispromoting conditions in vitro. Integration of transcriptome profiles from THRB KO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THR(B) manipulation in fatty liver diseases.
Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they... more 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. Thyroid hormones (THs) are important regulators of embryonic development and energy metabolism. Produced in the thyroid gland in response to stimulation of the hypothalamus-pituitary-thyroid axis, thyroxine (T 4) and, to a much lower extent, the biologically active 3,3' ,5-triiodothyronine (T 3) are secreted into the bloodstream. At target tissues, T 4 is converted into T 3 via specific deiodinases (DIOs). T 3 can bind to the two nuclear TH receptors (THR) alpha/THRA and beta/THRβ which act as transcription factors. As in most tissues, T 3 action in the liver is predominately exerted by one primary nuclear receptor, in this case, THRβ 1-3. THs effects in mammals are diverse and highly tissue specific. The thyroid state (i.e., systemic levels THs) profoundly affects energy metabolism with high THs levels correlating with lower body weight and increased thermogenesis, lipolysis, and glucose usage. In the liver, T 3 simultaneously induces de-novo lipid biosynthesis and, to a greater extent, lipolysis. Increased liver fatty acid (FA) uptake and turnover through beta-oxidation in mitochondria and peroxisomes are induced by T 3. Similarly, T 3 enhances cholesterol uptake, biosynthesis, and metabolization into bile acids, and it also increases hepatic gluconeogenesis and inhibits glycolysis and acetyl-coA utilization in the tricarboxylic acid (TCA) cycle 1,3,4. Low THs levels, found in subclinical and clinical
24-h rhythms in physiology and behaviour are orchestrated by an endogenous circadian clock system... more 24-h rhythms in physiology and behaviour are orchestrated by an endogenous circadian clock system. In mammals, these clocks are hierarchically organized with a master pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). External time signals-so-called zeitgebersalign internal with geophysical time. During shift work, zeitgeber input conflicting with internal time induces circadian desynchrony which, in turn, promotes metabolic and psychiatric disorders. However, little is known about how internal desynchrony is expressed at the molecular level under chronodisruptive environmental conditions. We here investigated the effects of zeitgeber misalignment on circadian molecular organisation by combining 28-h light-dark (LD-28) cycles with either 24-h (FF-24) or 28-h feeding-fasting (FF-28) regimes in mice. We found that FF cycles showed strong effects on peripheral clocks, while having little effect on centrally coordinated activity rhythms. Systemic, i.e., across-tissue internal circadian desynchrony was profoundly induced within four days in LD-28/FF-24, while phase coherence between tissue clocks was maintained to a higher degree under LD-28/FF-28 conditions. In contrast, temporal coordination of clock gene activity across tissues was reduced under LD-28/FF-28 conditions compared to LD-28/FF-24. These results indicate that timed food intake may improve internal synchrony under disruptive zeitgeber conditions but may, at the same time, weaken clock function at the tissue level.
ABSTRACTThyroid hormones (THs) are important regulators of systemic energy metabolism. In the liv... more ABSTRACTThyroid 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 l...
ObjectiveInternal clocks time behavior and physiology, including the gut microbiome in a circadia... more ObjectiveInternal clocks time behavior and physiology, including the gut microbiome in a circadian (∼24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown.MethodsCore and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus (Bmal1SCNfl/-), and wild-type mice exposed to simulated shift work (SSW). Body composition and energy balance were evaluated by nuclear magnetic resonance (NMR), bomb calorimetry, food intake and running-wheel activity. Intestinal permeability was measured in an Ussing cham...
Anatomie und Netzwerkorganisation im circadianen System
Auf der Suche nach der biologischen Zeit, 2020
In den 1990er-Jahren fuhrten bahnbrechende chirurgische Experimente zur Identifikation des SCNs a... more In den 1990er-Jahren fuhrten bahnbrechende chirurgische Experimente zur Identifikation des SCNs als primarem Schrittmacher des circadianen Systems. Dieser kommuniziert uber neuronale und kreislaufvermittelte Signale mit einem Netzwerk von Uhren im ganzen Korper. Diese Netzwerke der circadianen Uhren und Rhythmen sind ein vielversprechender Gegenstand zur Vorbeugung und Behandlung von vielen chronischen Krankheiten, darunter Stoffwechsel- und Schlafstorungen, aber auch psychische Krankheiten wie die (Winter-)Depression oder sogar Krebs. Es wird dabei immer deutlicher, dass Zell- und Gewebeuhren unseres Korpers nicht unabhangig voneinander funktionieren. Ansatze zur circadianen Taktstabilisierung wie die Licht- oder Melatonin-Therapie mit dem Ziel, so die gesamte Netzwerkorganisation des Uhrensystems zu beeinflussen, konnen die Pravention oder Behandlung von Krankheiten erleichtern.
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Papers by Henrik Oster