Study Questions Lecture 08

TH transporter protein in plasma membrane (e.g., MCT8)
- Facilitates the transport of thyroid hormones T4 and T3 across the plasma membrane into target cells.
De-iodinase 1 or 2 inside target cell
- Enzymes that convert T4 (thyroxine) to T3 (triiodothyronine), the active form of the hormone. De-iodinase 1 (DIO1) and De-iodinase 2 (DIO2) are crucial for regulating hormone levels within the cell.
TR subunit
- Thyroid hormone receptor (TR) subunit that binds thyroid hormones and mediates their physiological effects by regulating gene expression.
RXR subunit
- Retinoid X receptor (RXR) subunit that heterodimerizes with TR, playing a role in gene regulation by thyroid hormones.
TRE (Thyroid Response Element)
- Specific DNA sequences located in gene promoters that bind TRs and RXR to regulate gene transcription in response to thyroid hormone signaling.
Co-Repressors
- Proteins that bind to TRs in the absence of hormone and inhibit gene transcription.
CoActivators
- Proteins that enhance the transcriptional activity of TRs when thyroid hormones are bound, facilitating gene expression.

Hormone binding domain
- The region of the TR that specifically binds thyroid hormones (T3 or T4) and initiates conformational changes necessary for gene activation.
DNA binding domain
- The portion of the TR that interacts directly with the TRE in the DNA, allowing the TR to regulate gene expression.
TRE (Thyroid Response Element)
- Specific DNA sequences that TR binds to; critical for the regulation of gene expression in response to thyroid hormone levels.

Definition
- A complex network of genes influenced by thyroid hormones through primary response genes governing a variety of cellular processes.
Follow-up concept
- Despite the 100-200 primary response genes directly affected by T3, there may be 5-10 times that number of genes regulated indirectly via secondary and tertiary responses. These additional genes are referred to as secondary response genes or indirectly regulated genes.

Pax8 KO mouse
- A mouse model that lacks the Pax8 gene, essential for normal thyroid gland development. These mice typically exhibit hypothyroidism and severe defects in thyroid development.
TR alpha KO mouse comparison
- TR alpha knockout mice generally reflect normal thyroid function compared to Pax8 KO, despite TR alpha being abundantly expressed in the brain, this observation is surprising because one would expect a pronounced impact on brain development due to the absence of TR alpha.
TR alpha receptor with no hormone binding
- A TR alpha receptor engineered not to bind hormone and unable to release co-repressors highlights the necessity of thyroid hormones in brain development, suggesting they act both as activators and de-repressors in gene expression.

Disruption of HPT axis regulation
- TR beta knockout mice exhibit altered regulation of the hypothalamus-pituitary-thyroid (HPT) axis, affecting feedback mechanisms that control thyroid hormone production and release.
Relevance to heart rate
- Despite TR beta not being the main receptor in the heart (which expresses TR alpha), the higher heart rates in TR beta KO mice suggest a compensatory mechanism at play in the regulation of heart rate.

Finding
- The experiments demonstrate the role of thyroid hormone in regulating metamorphosis in amphibians, specifically how TH influences developmental transitions.

Consideration on T4 vs. T3
- Therapeutically, T3 is often preferred due to its higher potency and faster action compared to T4, thus making it likely easier to induce metamorphosis with T3.

Most sensitive structures
- Structures undergoing rapid developmental changes during metamorphosis, including the limbs and tail, are particularly sensitive to TH levels.
Least sensitive structure
- The brain typically shows a lower sensitivity to TH compared to limbs.
TR alpha expression absence implications
- Tadpoles lacking TR alpha expression are predicted to have inhibited limb development and altered brain development, consistent with TR alpha being an accelerator in metamorphosis initiation and progression.
TR beta absence predictions
- Lacking TR beta may impact TH actions differently, potentially affecting other developmental pathways.

First secretion
- Thyroid hormone (TH) begins secretion during fetal life, and levels peak shortly after birth.
TSH levels in newborns
- High TSH levels in newborns can indicate primary hypothyroidism, making immediate testing vital for timely intervention.

General Effects
- Promotes normal brain development and function, influences neuronal growth, differentiation, and maturation.
Specific Neuronal Cell Type
- Thyroid hormones specifically impact granule cells in the developing hippocampus, enhancing synaptic plasticity and cognitive function.

Common symptoms
- Goiter, hypothyroidism, cognitive impairments, and developmental delays in children.
Preventative measures
- The most successful global effort has been the iodination of salt, dramatically reducing deficiency cases.

Major Differences
- Endotherms (warm-blooded) utilize TH for metabolic regulation, energy expenditure, and thermogenesis; ectotherms (cold-blooded) primarily use TH to regulate growth and development processes.

Key aspects
- Regulates basal metabolic rate (BMR), thermogenesis, lipid, carbohydrate, and protein metabolism, promoting energy homeostasis.

Impact on epinephrine response
- TH enhances the responsiveness of target tissues to epinephrine, improving energy mobilization responses during stress or activity.

O2 demand meeting
- Enhances oxygen consumption and cardiac output, preparing the organism for increased physical activity.

Energy demand meeting
- Increases the availability of glucose and fatty acids through enhanced metabolism, ensuring sufficient energy substrates during heightened demand versus resting states.

Definition
- A type of adipose tissue involved in thermogenesis, utilizing thyroid hormones to stimulate hormone-sensitive lipase for heat production.
TH Effects on BAT
- Increases the expression of thermogenic uncoupling proteins, facilitating non-shivering thermogenesis and overall metabolic rate elevation in response to cold exposure.