Lecture 9- Thyroid Hormone: thyroxine (T4) and triiodothyronine (T3)

Mechanism of activation

T4 secreted from follicular cells, circulation, peripheral tissue where T4 is converted to T3 via tyrosine deiodinase

TH suppresses

PRL during metamorphosis possibly by promoting acquisition of function PRL-inhibiting factor neurons

Which is the active thyroid hormone?

T3

Thyronine prealbumin binding protein (TBPA)

T3 and T4 bind to this in the blood

How is a hydrophobic molecule stored in the aqueous cytosol?

T3 and T4 is synthesized from tyrosine that are already incorporated into a protein that is hydrophilic. Residues are hydrophobic but entire protein is hydrophilic

Amphibian metamorphosis

Thyroid hormones stimulate morphological changes that transform aquatic larval stage amphibian to terrestrial animal

Addition of TH in amphibians and flatfish

accelerate metamorphisis

Enzymatic cleavage

allows T4 and T3 to be released from TG where they diffuse through the follicular plasma membrane into the circulation

TH stimulates salmon smoltification

along with GH and cortisol and migration to sea- may be initiated by a spring lunar cycle that induces thyroid surge during smoltification

PRL

anti-metamorphic (larval growth hormone) and antagonizes actions of thyroid hormone on metamorphosis in amphibians

Hydrophobic molecules (lipid soluble like steroids)

but they are not made as needed like steroid hormones. The thyroid gland cannot make T4 and T3 as needed because the essential ingredient iodine is not always available

Thyroid hormones: T3 and T4

composed of iodinated tyrosine (iodine is added to aa)- T3 with 3 iodines and T4 with 4

Hypothyroidism

dec TH, low basal metabolic rate, lowered body temp, lower pulse, cold intolerance, weight gain, loss of hair, lethargy/depression/tiredness, goiter may or may not be present

Salmon smoltification

developmental stage whereby parr fw fish transform to smolts (silvering- deposition of guanine in scales, sw tolerance, gut changes- more carnivorous) which then migrate to sea

Hyperthyroidism

elevated TH, inc metabolic rate, inc body temp, rapid pulse, heat intolerance, weight loss, muscle wasting, nervousness/anxiety/insomnia, goiter present

Hyperthyroidism- thyrotoxosis

excess TH

Cyanogenic glucosides

found in cassava, sorghum, sweet potatoes, maize, apricots, cherries are hydrolyzed by glucosidases in gut to produce thiocyanates (goitergens)

Thyroglobulin (TG)

hydrophilic protein that has T3 and T4 incorporated into that is synthesized from tyrosine.

Plants of genus Brassica

include cabbage, brussel sprouts, turnups, rutabagas contain progoitrin which is converted via the enzyme, tyrosinase, to goitrin

Removal of thyroid in amphibians and flatfish

inhibits metamorphosis and addition

Colloid

inner colloidal material

Childhood hypothyroidism- cretinism

lack of skeletal growth and maturation, retardation

Adult hypothyroidism- myxedema

mucus deposits on subcutaneous tissues

Mechanism of action of TH

occurs through mainly binding nuclear receptors and activating transcription with receptor heterodimers being most potent in regulating gene transcription, thyroids may also act directly on mitochondria or plamsa membranes to rapidly induce enzyme activity through nongenomic mechanisms of action

Grave's disease

protruding of eyes, goiter. Results in overstimulation of thyroid caused by thyroid stimulating antibodies that activate the TSH receptor by acting like TSH

Lack of T4/T3

results in little negative feedback of TSH, so excess TSH causes proliferation (hyperplasia) and enlargement of follicles (hypertrophy)

Natural foods

some are also goitergens

Antithyroid drugs

suppress thyroid hormone synthesis by inhibiting iodide uptake, iodide oxidation (activation) or iodination of thyroid hormone. Effectively cause thyroid glands to enlarge or are goitergens

Follicular cells

thyroid follicle cells that are composed of epithelial cells, surrounds inner colloidal material

Fish metamorphosis

thyroid hormones stimulate morphological changes that transform flounder/halibut or flatfish from a bilateral larval fish in the water column to a benthic flatfish with both eyes on one side of the body. Head restructures, eyes migrate, dorsal fin reabsorbs

Stored in thyroid gland

unlike steroids, thyroid hormones are made and stored in thyroid gland

Lines of investigation indicating T3 is the active hormone

1) T3 is more potent in inducing a physiological response 2) T3 binds receptors with higher affinity 3) reduced circulating T3 results in symptoms of hypothyroidism, even though T4 levels are normal 4) 5'-deiodinase inhibitor (PTU inhibits this as well as peroxidase) blocks biological actions of T4 (converts T4 to T3)

Synthesis of thyroid hormone

1) TSH binds a GPCR to stimulate cAMP production 2) inc activity of synthetic machinery and production and/or activation of Na+-I- symporter (drives I uptake in follicle), TG, peroxidase and other proteins involved in thyroid production 3) O2 consumption in thyroid tissue is increased, glucose uptake inc, pentose- PO4 cycle is activated for production of peroxidase 4) peroxidase oxidizes and activates iodine so it can be coupled to TG tyrosine residues within colloid 5) TG coupled to T4/T3 within colloid droplets is then endocytose by follicle cells 6) The colloid cells fuse with lysosomes and T4/T3 are cleaved from TG 7) free T4/T3 diffuses into blood 8) Iodotyrosines within lysosome are deiodinated by deiodinase to yield free iodide, which is recycled to produce more TH

Anatomy of thyroid gland

1) lobe located in throat just below the larynx 2) derived from endoderm of alimentary canal 3)exists as diffuse cells in lower vertebrates such as the teleost fishes 4) contains follicle cells that are interspersed with C-cells (secrete calcitonin)

Thyroid hormone action

1) stimulates overall metabolic rate 2) thermoregulator- induces ATP hydrolysis via activation of Na+-ATPase pump with heat being liberated and O2 consumed 3) inc growth- permissive hormone 4) stimulates development (needed for brain development, works with PRL on mammary gland development) 5) stimulates production of other hormone receptors and a variety of metabolic proteins and enzymes 6) permissive hormone- one that is required for the full activity of other hormones (PRL, GH, glucocorticoids and catecholamines) 7) stimulates migration of fish 8) stimulates smoltification in salmon (fw parr --> sw smolt)

Regulation

1)TSH stimulates thyroid hormone production 2) cold exposure stimulates TSH in mammals- suggested that homeothermy evolved in birds/mammals with thermogenesis (heat production) as thyroid hormone is not a major regulator of metabolic rate in most poikilotherms 3) inc caloric intake or short term over feeding stimulates thyroid hormones and diet induced thermogenesis