Thyroid-2 Regulation and Mechanism of Action lecture NO : 02 MBBS Dr Muhammad Ramzan

Regulation of THs Regulation of TH is important to: Control the metabolic activities of all the body cells Promotes the body growth especially CN development in children Provide energy to satisfy the requirements of all body reactions Maintain BMR for essential body systems like CVS; Respiratory.GIT and maintenance of body temperature

Regulation of THs TH are regulated through 2 path ways: Neuro endocrine regulation / Hypothalamus- pituitary Thyroid axis or Indirect pathway Pituitary - Thyroid axis/direct pathway Negative feed back is the main mechanism

Neuro endocrine pathway Serum TH level is the key player in regulation of the TH The deficiency of TH stimulates the hypothalamus to secrete Thyrotropin releasing hormone – TRH TRH stimulates the Ant. Pituitary to secrete TSH that stimulates the thyroid gland to ↑TH (T4) Opposite is true when serum TH level is high Exposure to cold in children ↑ release of TRH –TSH and TH

Pituitary- thyroid axis/ Direct pathway TH and TSH It is the interaction B/W TH level and Pituitary gland Deficiency of TH causes the stimulation of Pituitary to increase the secretion of TSH TSH stimulates and ↑ the secretion of TH from Thyroid Opposite is true when TH is high Hypothalamus/TRH has no role in this regulation

Regulation of TH – Both pathways

TH - regulation

TH – mechanism of action TH hormones act through activation of genes similar to that of Steroids hormones TH have nuclear receptors – Retinoid X receptors that bind with the TH to form hormone receptor complex(HRC) HRC is translocated to the acceptor site at the nucleus Hormone Response Element HRE - the gene for TH HRE is expressed for mRNA which translates enzymes/proteins that execute hormonal actions

Transport of Thyroid hormones (TH) TH are transported in free as well in bound form with plasma proteins Only a small fraction of TH is available in free form and is biologically active T3 is 10 times more active than T4

TH - Membrane transport and cytoplasmic de iodination Thyroxin/T4 must be de iodinated to Free T3(FT3) in the cytoplasm by Deiodinase before its : Translocation to the nucleus TH cross the cell membrane via the carrier mediated transporters – Iodothyronine Transporters This is active transport and ATP dependent

Bound form of TH – the significance Bound forms are attached to the Thyroxin Binding Globulin (TBG), Thyroxin Binding Pre albumen and Albumen Bound forms are important in measuring the activity of gland

TH - Mechanism of Action TH cross the cell membrane by Iodothyronine transporters to reach the acceptor site in the nucleus Thyroxin or T4 is de Iodinated first to T3 as active TH Bind first with the Retinoid X receptor (RXR) and then with the Hormone Response Element (HRE) at DNA Stimulates the TH genes (HRE) to transcribe mRNA that finds its way to the cytoplasm

TH - Mechanism of action cont. mRNA translates the specific proteins/ enzymes that carry out hormone effects/actions on the : Target cells throughout body TH Promote the growth, metabolism and activities of other systems (CV,respiratory and body temperature)

TH - Mechanism of action

Mechanism of TH

General actions of TH Stimulate the genetic expression at HRE Promote the synthesis of proteins and enzymes to promote growth, reproduction and repair TH increases the metabolic rate of body cells, energy release and maintain the body temperature

Metabolic actions of TH TH have significant metabolic actions on the : Protein metabolism Fat metabolism Carbohydrate metabolism and Maintenance of Body temperature, BMR and heat

Actions on Protein metabolism Promotes genetic expression; DNA replication,DNA content, increases the no of cells for body growth and repair TH promote protein synthesis, body growth and development of CNS especially in children Prevents proteolysis protein hormnes

Action on lipid metabolism TH stimulates Lipid metabolism Promotes lipolysis and ↑release of FAs from adipose tissues Reduces adipose tissue mass/ Lipogenesis Increases FA oxidation by ↑no of Mitochondria and activity Plasma level of TG and CH is inversely proportional to the TH level

Actions on carbohydrate metabolism Thyroid hormones stimulate Carbohydrate metabolism: Promotes the absorption of glucose from GIT Increases glycolysis and glucose utilization and reduces blood glucose level - hypoglycemic Promotes Glycogenolysis Produces hyperglycemia : Prevents Insulin secretion and promotes insulin degradation