7.3 Thyroid hormones and metabolic regulation

Thyroid hormones, primarily T4 and T3, play a crucial role in regulating metabolism. These iodine-containing molecules are synthesized in the thyroid gland and affect nearly every tissue in the body, influencing energy expenditure, growth, and development.

The hypothalamic-pituitary-thyroid axis controls thyroid hormone production through a negative feedback loop. This system maintains hormone balance, adjusting levels in response to the body's needs and environmental factors. Understanding thyroid function is key to grasping metabolic regulation.

Thyroid Hormone Synthesis and Secretion

Structure and Components

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• Thyroid hormones consist primarily of thyroxine (T4) and triiodothyronine (T3) derived from iodine-containing amino acids synthesized from tyrosine residues
• Thyroid gland contains follicles lined with epithelial cells producing thyroglobulin, a large glycoprotein precursor for thyroid hormones
• Sodium-iodide symporter (NIS) actively transports iodide into thyroid follicular cells
• Thyroid peroxidase (TPO) oxidizes iodide to iodine within follicular cells

Synthesis Process

• Iodination of tyrosine residues in thyroglobulin produces monoiodotyrosine (MIT) and diiodotyrosine (DIT)
• MIT and DIT couple to form T3 and T4 hormones
• Thyroid hormones remain stored within follicular lumen as part of thyroglobulin
• Proteolysis releases thyroid hormones from thyroglobulin for secretion into bloodstream
• T4 serves as primary hormone secreted by thyroid gland (approximately 80% of thyroid hormone output)
• T3 mostly produced through peripheral deiodination of T4 in target tissues (liver, kidneys)

Hormone Transport and Activation

• Thyroid hormones circulate bound to transport proteins (thyroxine-binding globulin, transthyretin, albumin)
• Free hormone fraction (unbound) represents biologically active form
• Deiodinase enzymes convert T4 to T3 in peripheral tissues
  • Type 1 deiodinase (D1): found in liver, kidneys, thyroid
  • Type 2 deiodinase (D2): found in brain, pituitary, brown adipose tissue
• T3 exhibits higher affinity for thyroid hormone receptors compared to T4

Hypothalamic-Pituitary-Thyroid Axis

Components and Signaling Cascade

• Hypothalamic-pituitary-thyroid (HPT) axis functions as negative feedback system maintaining thyroid hormone homeostasis
• Hypothalamus produces thyrotropin-releasing hormone (TRH)
• TRH stimulates anterior pituitary to secrete thyroid-stimulating hormone (TSH)
• TSH binds to receptors on thyroid follicular cells promoting thyroid hormone synthesis and secretion
• Circulating thyroid hormones (primarily T3) exert negative feedback on hypothalamus and anterior pituitary
  • Inhibits TRH production in hypothalamus
  • Suppresses TSH production in anterior pituitary

Regulation and Sensitivity

• HPT axis demonstrates high sensitivity to changes in thyroid hormone levels
• Small fluctuations trigger compensatory responses maintaining physiological concentrations
• Factors influencing HPT axis and thyroid hormone regulation
  • Stress (increases cortisol, affects TRH and TSH release)
  • Illness (alters peripheral conversion of T4 to T3)
  • Medications (lithium, amiodarone interfere with thyroid function)
• Diurnal variations in TSH secretion occur with highest levels at night and lowest levels during the day

Pathological Conditions

• Hypothyroidism results from insufficient thyroid hormone production or action
  • Primary: thyroid gland dysfunction (Hashimoto's thyroiditis)
  • Secondary: pituitary TSH deficiency
  • Tertiary: hypothalamic TRH deficiency
• Hyperthyroidism occurs due to excessive thyroid hormone production or action
  • Graves' disease (autoimmune stimulation of thyroid gland)
  • Toxic multinodular goiter
  • Thyroiditis (inflammation causing hormone release)

Thyroid Hormone Effects on Metabolism

Basal Metabolic Rate and Energy Expenditure

• Thyroid hormones serve as primary regulators of basal metabolic rate (BMR)
• Increase oxygen consumption and heat production in most tissues
• T3 stimulates mitochondrial biogenesis enhancing ATP production
• Promote expression and activity of various metabolic enzymes (Na+/K+-ATPase)
• Elevate energy expenditure through multiple mechanisms
  • Increased cellular respiration
  • Enhanced thermogenesis (especially in brown adipose tissue)
  • Augmented cardiovascular function (increased heart rate and cardiac output)

Carbohydrate Metabolism

• Thyroid hormones influence glucose homeostasis
• Promote glucose uptake and utilization in peripheral tissues
• Stimulate glycogenolysis (breakdown of glycogen to glucose)
• Enhance gluconeogenesis (glucose production from non-carbohydrate sources)
• Increase insulin sensitivity in skeletal muscle and adipose tissue
• Accelerate intestinal glucose absorption

Lipid Metabolism

• Thyroid hormones affect various aspects of lipid metabolism
• Increase lipolysis (breakdown of triglycerides into free fatty acids)
• Enhance fatty acid oxidation for energy production
• Stimulate cholesterol synthesis and degradation
• Upregulate LDL receptor expression promoting cholesterol clearance
• Influence bile acid synthesis and excretion

Protein Metabolism

• Thyroid hormones modulate protein turnover
• Promote both protein synthesis and breakdown
• Result in net catabolic effect at high concentrations
• Enhance amino acid uptake and utilization in tissues
• Influence growth hormone and insulin-like growth factor-1 (IGF-1) signaling

Thyroid Hormone Action and Targets

Target Tissues and Physiological Effects

• Thyroid hormones affect virtually all tissues in the body
• Brain: crucial for normal development, cognitive function, and mood regulation
• Heart: increase heart rate, contractility, and cardiac output
• Skeletal muscle: enhance protein synthesis, contractility, and energy metabolism
• Liver: stimulate lipogenesis, cholesterol metabolism, and gluconeogenesis
• Adipose tissue: promote lipolysis and thermogenesis (especially in brown adipose tissue)
• Bone: regulate bone formation and resorption (important for skeletal development)
• Gastrointestinal tract: increase gut motility and nutrient absorption

Cellular Mechanisms of Action

• Primary mechanism involves binding to nuclear thyroid hormone receptors (TRs)
• TRs function as ligand-activated transcription factors
• T3 exhibits higher affinity for TRs compared to T4
• TR binding process:
  • T3 enters cell and binds to TR in nucleus
  • TR forms heterodimer with retinoid X receptor (RXR)
  • TR-RXR complex interacts with thyroid hormone response elements (TREs) in target genes
  • Interaction leads to recruitment of coactivators or corepressors
  • Modulates gene expression and protein synthesis

Non-Genomic Actions and Local Regulation

• Non-genomic actions of thyroid hormones identified
• Involve plasma membrane receptors and rapid signaling pathways
  • Activation of mitogen-activated protein kinases (MAPKs)
  • Modulation of ion channels and transporters
• Tissue-specific deiodinases regulate local T3 availability
  • Type 1 deiodinase (D1): liver, kidney, thyroid
  • Type 2 deiodinase (D2): brain, pituitary, brown adipose tissue
  • Type 3 deiodinase (D3): placenta, brain (inactivates T4 and T3)
• Allow for fine-tuned control of thyroid hormone action in different tissues
• Polymorphisms in deiodinase genes may contribute to individual variations in thyroid hormone sensitivity