Publications by authors named "Jens Mittag"
Hepatic thyroid hormone action plays an important role in preventing the development and progression of metabolic liver diseases, as evidenced by the recent success of the receptor-specific agonist resmetirom. The liver enzyme deiodinase type I (DIO1) is important for controlling the local availability of thyroid hormone and is upregulated in metabolically associated steatotic liver disease (MASLD), which is thought to be a compensatory mechanism to enhance local hormone action. However, it remains unclear whether this increase is maintained in later stages of MASLD and whether an induction of Dio1 can provide beneficial metabolic effects.
View Article and Find Full Text PDFThyroid 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.
View Article and Find Full Text PDFObjective: Hypothalamic energy sensors, such as AMP-activated protein kinase (AMPK), and stress sensors, such as c-Jun N-terminal kinase 1 (JNK1, also known as MAPK8) modulate whole body energy balance. While the role of AMPK in steroidogenic factor 1 (SF1) neurons of the VMH has been investigated, the relevance of JNK1 in this neuronal population has not been addressed. Here, we investigated the involvement of JNK1 SF1 on energy homeostasis.
View Article and Find Full Text PDFThyroid hormone receptor α1 (TRα1) regulates body temperature and heart rate in humans and mice. In addition to its direct actions in target tissues, it also affects peripheral functions indirectly through the brain. While these central actions on peripheral tissues have been demonstrated for liver and brown fat, the consequences for cardiac functions are still enigmatic.
View Article and Find Full Text PDFHypothalamic control of heart rate and body temperature by thyroid hormones.
Rev Endocr Metab Disord
April 2025
As evidenced by the clinical symptoms in hyper- or hypothyroidism, thyroid hormones have strong effects on cardiovascular and metabolic functions. While these actions had been initially attributed to direct molecular mechanisms in the respective peripheral tissues such as heart, muscle or adipose tissue, a recent paradigm shift has occurred with accumulating observations that demonstrated important indirect effects via the brain on these systems. However, the individual contributions of the peripheral versus central thyroid hormone actions for the well-known phenotypical symptoms are still not entirely understood.
View Article and Find Full Text PDFSex-specific role of epigenetic modification of a leptin upstream enhancer in adipose tissue.
Clin Epigenetics
February 2025
Objective: Maternal hormonal status can have long-term effects on offspring metabolic health and is likely regulated via epigenetic mechanisms. We elucidated the effects of maternal thyroid hormones on the epigenetic regulation of leptin (Lep) transcription in adipose tissue (AT) and subsequently investigated the role of DNA methylation at a Lep upstream enhancer (UE) in adipocyte biology.
Results: Pregnant mice treated with triiodothyronine (T3) produced offspring with reduced body weight, total fat mass, and gonadal white adipose tissue (gWAT) mass at 6 months of age (treatment: N = 8; control: N = 12).
The significance of thyroid hormones (THs) in beige adipocyte thermogenesis remains incompletely understood. We previously reported that THs directly regulate the expression of zinc-finger protein 423 (ZFP423), an anti-thermogenic factor, in adipose tissue. This study investigates the interaction between THs and adrenergic signaling in regulating thermogenic capacity and activation of beige adipocytes formed in response to Zfp423 deletion.
View Article and Find Full Text PDFSerum CD5L as potential biomarker of thyroid hormone status during pregnancy.
Biofactors
December 2024
Article Synopsis
- The study examines the potential of serum CD5L, a liver-derived protein, as an additional biomarker for assessing thyroid hormone (TH) status during pregnancy, where routine markers may change.
- Researchers developed a sensitive assay to measure CD5L levels and investigated factors that might influence its concentrations, finding that it remained stable and unaffected by circadian rhythms or liver disease.
- Results showed that CD5L positively correlated with free triiodothyronine (fT3) and trace elements like selenium and copper in pregnant women, suggesting its potential usefulness as a reliable TH status indicator, especially in pregnancy and thyroid-related conditions.
Article Synopsis
- Metabolic dysfunction-associated steatohepatitis (MASH) is linked to inflammation and fatty liver, and its progression may be influenced by reduced thyroid hormone signaling, specifically through decreased DIO1 and THRB expression.
- Research revealed that miR-34a-5p is increased in MASH patients and may play a role in suppressing thyroid hormone activity in the liver by targeting genes like THRB and DIO1.
- Additionally, DNA methylation changes in the THRB gene were found in MASH patients, potentially contributing to a state of resistance to thyroid hormones as the disease progresses.
Article Synopsis
- Thyroid disease impacts energy metabolism, temperature control, and anxiety, primarily through thyroid hormone receptor α1 (TRα1) in the brain, but the exact brain areas involved remain unclear.
- Researchers used PET-CT scans to find the most affected brain region, the zona incerta (ZI), and inhibited TRα1 signaling there to study its effects on metabolism and behavior in mice.
- The inhibition led to increased energy expenditure without affecting body temperature regulation, and heightened glucocorticoid levels were observed, indicating a link between altered thyroid hormone signaling in the ZI and stress responses, but not temperature control.
Article Synopsis
- Thyroid hormone significantly influences cardiovascular functions, particularly heart rate, through both direct genetic mechanisms and indirect effects on the autonomic nervous system.
- The review examines recent findings regarding the roles of different thyroid hormone receptor isoforms in heart rate regulation, questioning the traditional view that pacemaker channel genes Hcn2 and Hcn4 are the only mediators of these effects.
- It also highlights the importance of considering long-term impacts of altered thyroid hormone action during development on both heart and brain functions in experimental designs.
Article Synopsis
- The study investigates the effects of thyroid hormones (TH) on cardiac function, specifically focusing on which thyroid hormone receptors (TR) mediate these effects and through which mechanisms.
- Researchers compared mice with knockout versions of TRα and TRβ receptors to wild-type mice and assessed heart changes after treatment with T3, a form of thyroid hormone.
- Results showed that T3-induced ventricular hypertrophy primarily involved noncanonical TRα action, while heart rate regulation was mainly governed by canonical TRα action, with TRβ being able to compensate for some TRα functions.
Article Synopsis
- Thyroid hormones influence heart functions by binding to specific receptors, primarily TRα1 and TRβ, but the role of TRβ is not well understood due to complications from hyperthyroidism in TRβ knockout mice (TRβ-KO).
- Researchers studied TRβ-KO mice at controlled temperatures to eliminate hyperthyroid effects, finding normal heart rates but impaired parasympathetic activity, particularly at lower temperatures.
- T3 treatment caused tachycardia in wild-type mice, but TRβ-KO mice showed a limited response, revealing TRβ’s important but less understood role in heart function at thermoneutrality.
Cardiac recovery from pressure overload is not altered by thyroid hormone status in old mice.
Front Endocrinol (Lausanne)
March 2024
Article Synopsis
- Thyroid hormones (THs) are important for heart health, but their effects on older mice with existing heart issues remain unclear, especially in the context of conditions like hypertension and aging.
- A study found that manipulating TH levels in aged mice with heart damage (induced by transverse aortic constriction) showed minimal effects on heart function and structure, contrasting with significant changes seen in younger mice.
- The researchers noted altered expressions of certain genes related to TH metabolism and action in older mice, which might explain the reduced responsiveness of their hearts to thyroid hormone levels.
Article Synopsis
- Thyroid hormones (THs) play a crucial role in regulating energy metabolism, particularly in the liver, where they influence lipid and cholesterol levels as well as overall energy availability.
- A study using a mouse model of hypothyroidism found that low TH levels reduced activity, food intake, and body temperature primarily during the active phase, with minimal effects on liver gene expression compared to high TH levels.
- Circadian analysis revealed changes in gene expression patterns related to cholesterol metabolism in low-TH mice, identifying 516 genes as potential markers for assessing liver TH state throughout the day.
Article Synopsis
- Thyroid hormones play a crucial role in regulating body temperature and energy metabolism, with medical conditions like hyperthyroidism and hypothyroidism directly affecting these processes.
- Recent research highlights the roles of specific thyroid hormone receptors, particularly TRα1 and TRβ, in body temperature regulation, although the exact functions and brain areas involved are still unclear.
- Experiments using mutant TRα1 mice and TRβ knockouts showed that TRα1 is vital for maintaining body temperature, with T3 treatment being effective in normalizing temperature in mutant mice, indicating it's crucial for setting the central temperature in the hypothalamus.
Article Synopsis
- Maternal thyroid hormones significantly influence fetal development, but the effects of maternal hyperthyroidism on offspring are not well understood.
- In a mouse study, maternal treatment with the thyroid hormone T3 during pregnancy improved glucose tolerance in male offspring and increased thermogenesis in brown adipose tissue (BAT) in both sexes.
- The study found that proper maternal thyroid hormone receptor β (TRβ) signaling is crucial for these benefits, and alterations in maternal serum metabolites like choline were also observed, linking maternal TRβ activation to specific adaptations in offspring thermoregulation.
Article Synopsis
- Agonists targeting thyroid hormone receptor β (TRβ) have shown potential in treating non-alcoholic fatty liver disease in earlier studies, but recent findings indicate a decrease in TRβ expression in severe cases like non-alcoholic steatohepatitis (NASH), which may hinder their effectiveness.
- A mouse study using a specific diet model confirmed a decline in TRβ during NASH development, but surprisingly, mice without TRβ had less liver damage and lower levels of NASH-related genes.
- Gene therapy that boosted TRβ in normal mice with NASH did not lead to improvements in liver condition or metabolic health, suggesting that the role of TRβ may be less significant than expected and that treatments should focus more on
Mutations in thyroid hormone receptor α1 (TRα1) cause Resistance to Thyroid Hormone α (RTHα), a disorder characterized by hypothyroidism in TRα1-expressing tissues including the heart. Surprisingly, we report that treatment of RTHα patients with thyroxine to overcome tissue hormone resistance does not elevate their heart rate. Cardiac telemetry in male, TRα1 mutant, mice indicates that such persistent bradycardia is caused by an intrinsic cardiac defect and not due to altered autonomic control.
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- The hypothalamic pituitary thyroid axis plays a crucial role in managing differentiation processes, including how fat cells develop, but the exact role of thyroid hormones (TH) in this process is still not fully understood.
- This study demonstrates that thyroid hormones directly influence the transcription of zinc finger protein 423 (Zfp423), which is essential for the early development of fat cells, in mouse fat tissue.
- Findings reveal that Zfp423 not only responds to thyroid hormones but also affects gene programs related to fat cell formation, highlighting its importance in how thyroid signaling affects the flexibility of fat tissue.
Article Synopsis
- The study investigates how thyroid hormone and its receptor TRα1 influence brain development, particularly in the hypothalamus, using a mouse model with a specific mutation that causes hypothyroidism.
- Researchers used single-nucleus RNA sequencing to analyze the effects of defective TRα1 signaling, finding it notably impacts hypothalamic oligodendrocytes but not other neuronal populations.
- The results highlight the importance of early postnatal thyroid hormone for the maturation of hypothalamic oligodendrocytes and provide insights into the role of thyroid health in brain development.
Article Synopsis
- Thyroid hormones (THs) are crucial for regulating energy balance, thermogenesis in brown adipose tissue (BAT), and body temperature, but their effects vary between species, as seen in hyperthyroid patients.
- The study examined how different environmental temperatures (23°C, 4°C, and 30°C) impact the effects of THs administered to rats, specifically looking at L-thyroxine (T4) and triiodothyronine (T3) treatment.
- Results indicated that the influence of both T4 and T3 on energy balance and BAT thermogenesis is significantly affected by temperature, emphasizing the importance of considering temperature and species differences in thyroid hormone research.
Article Synopsis
- Allan-Herndon-Dudley syndrome, caused by a deficiency in the MCT8 transporter, leads to significant X-linked intellectual and motor disabilities due to impaired transport of thyroid hormones to the brain.
- Current treatments can improve physical symptoms but do not address neurological issues, prompting research into gene replacement therapy in mouse models.
- The study found that targeting Mct8 expression in brain endothelial cells via gene therapy improved thyroid hormone levels in the brain and resulted in lasting enhancements in motor skills, highlighting a potential therapeutic approach for this condition.
Article Synopsis
- Diurnal physiological rhythms are regulated by circadian clock genes/proteins and influenced by various factors like temperature, food intake, and thyroid hormones (THs), which impact processes like energy metabolism.
- A study on mice indicated that high levels of triiodothyronine (T) affected body temperature and oxygen consumption in relation to the time of day, with 37 transcripts identified as potential markers for TH state in the liver.
- Analysis revealed that changes in the liver's transcript rhythms were mainly related to overall expression levels, and TH levels altered metabolic processes, leading to a loss of rhythmicity in genes related to glucose and fatty acid metabolism, indicating increased energy turnover in the liver.
Thyroid hormones (THs) control a wide range of physiological functions essential for metabolism, growth, and differentiation. On a molecular level, TH action is exerted by nuclear receptors (TRs), which function as ligand-dependent transcription factors. Among several TR isoforms, the function of TRα2 remains poorly understood as it is a splice variant of TRα with an altered C-terminus that is unable to bind T3.
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