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Endocrinology Final > Thyroid Hormones and Metabolism > Flashcards

Thyroid Hormones and Metabolism Flashcards

1
Q

Where is TRH synthesized?

A
  • In the PVN by hypophysiotropic neurons
  • Increases TSH secretions
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2
Q

Where is TSH synthesized?

A
  • TSH is a glycoprotein
  • Synthesized in the anterior pituitary (pars distalis) by thyrotrophs
  • Peptide component is synthesized under genetic control
  • alpha and beta subunits are synthesized separately
  • Rate limiting step: production of beta subunit
  • Glycosylation (attachment of carbohydrate moieties): post-ribosomal event, controlled by golgi enzymes
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3
Q

Why is TH an exception with signaling?

A

It acts via nuclear receptors

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4
Q

What information do TRH neurons integrate?

A

Information about the environment (temperature, energy storage, and stress)

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5
Q

TRH Signaling

A
  • TRH neurons project to other CNS areas (in addition to their effects on the anterior pituitary): Dorsal motile vagus (DMV) of the vagus nerve (GI motility)
  • TRH is present in peripheral tissues (ex: retina, pancreas)
  • Receptor is a GPCR
  • THR-R1 and THR-R2
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6
Q

THR-R1

A
  • Signals through Gq protein alpha subunit, induction of protein kinase C, phosphatidyl- inositol and calcium
  • PIP2 -> IP3 and DAG
  • IP3 diffuses into the ER (opens IP3 gated calcium channels on the ER)
  • DAG activates protein kinase C
  • Changes in gene expression
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7
Q

What stimulates TSH synthesis?

A
  • Cold, stress -> beta-adrenergic activation -> TSH secretions
  • TRH
  • Dopamine and somatostatin inhibits TSH secretions
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8
Q

What exerts a negative feedback loop on thyrotrophs?

A
  • Thyroid hormone
  • Modulates secretory activity
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9
Q

Thyroid Gland

A
  • Largest endocrine organ
  • Stores more of its hormones than any other glands
  • Secretes thyroxin T4 and its active derivative T3
  • Impact all metabolic pathways and organs (modulates oxygen consumption, BMR, lipids, carbs, and protein metabolism)
  • Affect nervous system (especially during development)
  • Regulate synthesis and degradation of other proteins and hormones
  • Every tissue express TR (T3 receptor)
  • Gland is divided into lobules, composed of follicles
  • Rich vasculature
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10
Q

Thyroid Hormones

A
  • Thyroxine T4
  • Triiodothyronine T3
  • Four and three organically bound iodine: intake of iodine is key for normal thyroid function
  • Iodine deficiency: delayed development, hypothyroidism, goiter
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11
Q

Thyroid gland follicle cells

A
  • Single epithelial layer
  • Colloid thyroid is a viscous proteinaceous solution and contains thyroglobulin (Tg)
  • Releases Tg
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12
Q

Thyroglobulin (Tg)

A
  • Storage form of TH and most abundant protein in the thyroid gland
  • Released from follicular cells by vesicular exocytosis
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13
Q

What cells secrete calcitonin?

A

Parafollicular cells (C cells): found in between follicles

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14
Q

Explain the synthesis of T3 and T4.

A
  • T3 and T4 are synthesized by incorporating iodine atoms into the tyrosine residues of thyroglobulin (Tg)
  1. Exocytosis of Tg from ER to follicle colloid
  2. Active transport of iodine into the follicular cells from blood via Na/I symporter (NIS)
  3. Transport of iodine from follicular cells to colloid via pendrin
  4. Oxidation of iodine via thyroid peroxidase and iodination of Tg; conjugation of iodotyrosine within Tg to form T4 and T3
  5. Phagocytosis back to the thyroid cell epithelium (colloid is engulfed by follicular cells pseudopods = micro/macropinocytosis) -> colloid droplets
  6. Colloid droplets fused with lysosomes
  7. Proteolysis of Tg and release of T4 and T3 -> free iodotyrosine and iodothyronines (endocytotic vesicles)
  8. Secretion of T4 and T3 into the cytoplasm via the MCT8 (monocarboxylate transporter 8) transporter (out of thyroid cell)
  9. Deionization of iodotyrosine (follicular cell or thyrocyte) to reutilize iodine
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15
Q

Explain the need for iodine.

A
  • Availability is limited, thyroid gland has evolved for ultimate utilization and conservation
  • GI iodine is reduced to iodide and actively accumulates in the thyrocyte
  • Thyrocyte can trap iodide at the base of cell and transport it against an electrical gradient
  • Unidirectional transport by membrane glycoprotein (NIS) (Na+/I- symporter): energy is required for active transport
  • TSH affects iodine uptake
  • TSH upregulates NIS transcription and post-translational maturation
  • Second protein (pendrin) transport iodide from basal membrane to the follicular lumen
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16
Q

What are the necessary steps for iodine incorporation?

A
  1. I- oxidation to Iox (peroxidase enzyme)
  2. Addition to Tg to tyrosine residues (monoiodotyrosine (MIT) or diiodotyrosine (DIT))
  3. Oxidative coupling of two residues (peroxidase enzyme): T4 and smaller amount of T3
17
Q

How do MIT and DIT create T3 and T4?

A
  1. T3: MIT + DIT
  2. T4: DIT + DIT
18
Q

Pendred Symptom

A
  • Mutations in the PDS gene, which codes for the pendrin protein
  • Hearing loss or deafness (often at birth and progressive)
  • Enlarged vestibular aqueduct (inner ear malformation)
  • Goiter (swollen thyroid at the base of the neck)
  • Hypothyroidism (underactive thyroid hormone which causes not enough thyroid hormone -> increased TSH production)
  • Speech impairment
  • Electrolyte/homeostasis imbalance
19
Q

How are the follicular cells impacted by chronic stimulation?

A

Smaller overall (smaller colloid, larger cells)

20
Q

How are the follicular cells impacted by infrequent stimulation?

A

Larger than normal (large colloid, smaller cells)

21
Q

Differentiation T3 and T4

A
  • T4 is about 70 times more concentrated in the blood than T3 (T3 in storage)
  • T4 has a greater half life (T4 is inactive and can be peripherally deiodinated to form T3)
  • Circulating T4: reservoir
  • T3 is the active form (signals via activation of nuclear receptors and changes in gene expression)
22
Q

How does T4 and T3 circulate?

A
  • Mostly bound to proteins:
  • TBG: thyroxine-binding globulin
  • TTR: transthyretin (or TBPA thyroxine-binding prealbumin)
  • Albumin
  • For hormone to be active, needs to be separate from protein
23
Q

What are the two main effects of thyroid hormone?

A
  1. Metabolism and regulation of basal metabolic rate (BMR)
  2. Cell growth and differentiation
24
Q

Thyroid Hormone Receptor

A
  • TR
  • TR has a much higher affinity for T3
  • Different isoforms of TR, expression varies based on tissues and developmental stage
  • TRbeta: chromosome 3 (isoform 1 and 2 -> bind to T3)
  • TRalpha: chromosome 17 (isoform 1 -> binds to T3)
  • beta1 and alpha1 are present in numerous tissues
  • beta2 is limited to the pituitary and CNS
  • TR can form a homodimer (forming a dimer with itself) or dimerize with other receptors (likes to dimerize with RxR)
25
Q

TR Signaling

A
  • Even without ligand, TR is associated with nuclear chromatin
  • TR can heterodimer with the retinoid X receptor: most common form
  • Absence of ligand TR-RXR represses gene expression
  • When activated by T3 -> coactivators replace corepressors -> transcription
  • Slow signaling (nuclear receptor)
26
Q

TR Independent Signaling

A
  • T3 can induce cellular changes very rapidly (used for quick energy)
  • Nuclear independent signaling
  • Binding sites for T3 on the plasma membrane have been identified as well as the inner mitochondrial membrane
  • Direct actions at the membrane include: increased AA uptake, increased glucose uptake
  • Actions on mitochondria: increased oxygen consumption (= increased cellular respiration -> increased energy)
27
Q

Basal Metabolic Rate (BMR)

A
  • BMR: energy expended to maintain basic function under thermal neutral condition
  • Proportional to body volume and oxygen consumption
  • T3 can increase the metabolic rate by increasing oxygen consumption (burning fuel) in muscles, liver, etc.
  • BMR can change depending on thyroid hormone status
  • T3 affects pathways involved in carb and lipid metabolism (directly and indirectly by modulating response to other hormone)
28
Q

How does T3 impact neurodevelopment?

A
  • TR is expressed throughout the fetus brain (important role in maternal TR)
  • thyroid gland appears during first trimester
  • T3 secretion detected in the second trimester
29
Q

Explain the negative feedback loops with TSH.

A
  • Thyrotroph have high levels of D2 (enzyme to convert T4 to T3)
  • T3 binding to its nuclear receptor TRbeta2 inhibits synthesis of beta subunit
  • T3 also decreases thyrotroph TRH receptor expression
    T4 inhibit secretion
  • Thyrotrophs are the main target for negative feedback
30
Q

Explain the negative feedback loops with TRH.

A
  • Activation of TRbeta2 inhibits TRH transcription
31
Q

Iodide-driven regulation (autoregulation)

A
  • If intake is greater than what is needed, Tg iodination is blocked (Wolff-Chaikoff effect: iodine- induced hypothyroidism)
  • If high intake persists, the thyroid gland will adapt and resume production (escape from the effect)
  • In individuals with autoimmune thyroid disease, the suppressive effect may persist
  • Large iodide amount can also block TH release
32
Q

Hypothyroidism

A
  • Enlarged thyroid gland (overstimulation of the TSH receptor)
  • Decreased heart rate, GI appetite, intestinal peristalsis, and BMR
  • Increased weight
  • Slow contractions and stiffness with skeletal muscles
  • Decreased nervous system (slow reflexes, memory loss, and lethargy)
33
Q

Explain the impact of hypothyroidism during development.

A

Impaired growth, reduction in GH

34
Q

Hyperthyroidism

A
  • Enlarged thyroid gland (goiter due to overstimulation of TSH receptor)
  • Increased heart rate, GI appetite, intestinal peristalsis, and BMR
  • Decreased weight
  • Increased nervous system (hyperkinesia, irritability, insomnia)
  • Wasting and weakness in skeletal muscle
35
Q

Thyrotoxicosis

A

Excess thyroid hormone (regarding of the source)

36
Q

Grave’s Disease

A
  • 50-80% of all thyrotoxicosis cases
  • More prevalent in women
  • Polygenetic disorder
  • Autoimmune disease production of antibodies against TSH receptor that act as agonists
  • Continuous TSH stimulation, little negative feedback
  • Ophthalmopathy (bulging of the eyes)
  • Treatment focuses in inhibiting T4 synthesis or iodide uptake
  • Surgical removal of the thyroid tissue also possible
37
Q

Hashimoto’s Disease

A
  • Most common cause of hypothyroidism in developed countries
  • Autoimmune disease
  • Antibodies attack thyroid gland cells
  • Destruction of follicles
  • Low circulating T3 and T4
  • Increased TSH release
  • Goiter

Endocrinology Final (13 decks)

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