The Thyroid Gland Butterfly shaped with two lobes right greater than left Size is proportional to metabolic activity also varies with iodine intake o Smaller in winter o Larger in pregnant women during lactation and puberty Rate of blood flow determine rate of thyroid hormones into circulation Two thyroid hormones T3 T4 regulate metabolism TSH binds thyrotropin receptors on thyroid follicle cells activates Gs Gq we will focus on Gs stimulates o Iodine uptake o Production and release of thyroid hormone o Thyroid growth Immediate response o Increased flux of I Na K o Protein kinase activation o Cellular metabolism Delayed response o Colloid processing o Thyroid hormone secretion TSH cAMP complex induces expression of genes for o Sodium iodide symporter NIS brings Na and I in together o Thyroglobulin Tg glycosylated protein is precursor for hormone o Thyroperoxidase TPO Epithelial aka follicular cells are arranged in spheres called thyroid follicles o Ring of cells surround colloid dense protein gel o Synthesize thyroglobulin which is stored in the colloid o Thyroid hormone released from Tg by exocytosis Parafollicular aka C cells secrete calcitonin which regulates blood calcium levels Iodine Thyroid hormone synthesis is the only physiologic role of iodine Iodine is scarce in environment so thyroid gland adapted to collect and store it Iodine deficiency impairs hormonogenesis Transport o Active cotransport with 2 Na across basolateral membrane by NIS o I is concentrated within follicular cells o Passive transport of I along concentration gradient into colloid through pendrin channels I Na Na Blood NIS basolateral membrane I Na Na I I I I I I pendrin apical membrane follicle I colloid Thyroperoxidase TPO uses H2O2 as oxidant to activate iodine then iodinates tyrosine residues of thyroglobulin Tg to form mono and diiodothyronine TPO combines MIT and DIT to form T3 and T4 and stored in colloid Endocytosis of colloid fusion to lysosome to form phagolysosomes w Exopeptidases allow release of T3 T4 from intermediates diffuse into endopeptidases that cleave Tg blood and bind carrier proteins Hydrolysis also releases MIT and DIT but these are metabolized I gets recycled and reused T3 and T4 are hydrophobic and thus utilize carrier proteins for circulation Mainly thyroxine binding globulin TBG a glycoprotein made by liver TBG affinity for T4 T3 Transethyretin TTR binds T4 but not T3 Albumin has low binding affinity but high serum concentration T3 and T4 can also bind HDL LDL Only free hormone is biologically active typically kept constant better measure of metabolic state than total hormone At the target tissue T4 is converted to T3 by 5 deiodination outer ring Major site of conversion is the liver There are three deiodinases Types I II III DI in liver kidney thyroid pituitary Generates circulating T3 for most peripheral target tissues DII in brain pituitary Also thyroid heart spinal cord skeletal muscle DIII in CNS skin placenta May inactivate T3 and T4 by removing I from placenta inner ring o Forms T2 from T3 o Forms rT3 from T4 which acts as an isomeric antagonist to T3 T3 circulating levels are typically lower than those of T4 it has a lower binding affinity to carrier proteins T3 has greater receptor affinity and is more active at tissues T4 is physiologically inactive because it does not enter nucleus in high enough concentration Thyroid Hormone Receptor Thyroid hormones can diffuse through cell membrane Three forms of thyroid hormone receptor o TR 1 widely expressed especially cardiac and skeletal muscle o TR 1 predominantly in brain liver and kidney o RR 2 primarily hypothalamus and pituitary TR 2 is widely expressed but does not bind hormone may act as antagonist because it weakly binds thyroid hormone response elements T3 binds receptor which pairs with nuclear protein partners such as retinoid X receptor RXR Complex binds thyroid hormone response elements to modify gene expression and influence mRNA stability Effects of T3 Increases basal metabolic rate in virtually all tissues Increases O2 consumption Increases body heat in peripheral tissue except brain gonads and spleen which are heat sensitive Cholesterol metabolism o Stimulate conversion of cholesterol to bile o Increases specific binding of LDL by liver cells o Thus LDL is rapidly removed from plasma o Hypothyroid high chol Stimulates carbohydrate and protein metabolism Needed for growth and development o Regulates endochondral bone formation in epiphyseal plates o May participate in osteoblast differentiation and proliferation by stimulating GH and IGF I Cognitive function mood behavior o CNS depends on T3 for maturation and function o Hypothyroidism can lead to mental retardation because it regulates neural development Reproductive system o Influences onset of puberty in females o Hypothyroidism linked to infertility o Pregnant women with hypothyroid at increased risk for miscarriage intrauterine fetal demise placental abruption etc Mitochondrial activity o In the presences of T3 a protein typically found in mitochondrial matrix binds TREs in mitochondrial DNA o T3 also increases expression of mitochondrial transcription factor TFA o Both stimulate mitochondriogenesis