7.3 Thyroid hormones and metabolic regulation
5 min read•august 16, 2024
Thyroid hormones, primarily T4 and T3, play a crucial role in regulating . 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 controls thyroid hormone production through a 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 (T4) and (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
- (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
- 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
- results from insufficient thyroid hormone production or action
- Primary: thyroid gland dysfunction (Hashimoto's thyroiditis)
- Secondary: pituitary TSH deficiency
- Tertiary: hypothalamic TRH deficiency
- 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 (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
Key Terms to Review (18)
Cardiovascular effects: Cardiovascular effects refer to the impacts that various factors, including hormones, have on the heart and blood vessels, influencing heart rate, blood pressure, and overall circulation. These effects are crucial in understanding how the body responds to different physiological and pathological states, particularly in relation to energy metabolism and homeostasis.
Deiodinase: Deiodinase refers to a family of enzymes responsible for the activation and deactivation of thyroid hormones through the removal of iodine atoms. These enzymes play a crucial role in the metabolism of thyroid hormones, particularly in converting thyroxine (T4) to the more active triiodothyronine (T3) and regulating overall metabolic processes. Their activity is essential for maintaining proper energy balance, growth, and development in response to thyroid hormone levels.
Gene Expression Regulation: Gene expression regulation refers to the complex mechanisms that control the timing, location, and amount of gene expression in a cell. This process ensures that genes are turned on or off as needed, allowing cells to respond to internal and external signals effectively. By modulating gene expression, organisms can manage various physiological processes, such as metabolism and response to hormones, which is particularly relevant in the context of metabolic pathways and regulation of substances like cholesterol and thyroid hormones.
Hyperthyroidism: Hyperthyroidism is a condition characterized by an overproduction of thyroid hormones, leading to an accelerated metabolism and various physiological changes in the body. This condition is often caused by autoimmune disorders, such as Graves' disease, and results in increased levels of circulating hormones like thyroxine (T4) and triiodothyronine (T3). The effects of hyperthyroidism on metabolism are profound, as the excess thyroid hormones stimulate various metabolic pathways, impacting energy levels, weight, and overall health.
Hypothalamic-pituitary-thyroid axis: The hypothalamic-pituitary-thyroid axis is a complex set of interactions between the hypothalamus, pituitary gland, and thyroid gland that regulates thyroid hormone production. This axis plays a crucial role in maintaining metabolic homeostasis by coordinating the release of thyroid hormones, which influence numerous physiological processes, including metabolism, growth, and development.
Hypothyroidism: Hypothyroidism is a medical condition characterized by an underactive thyroid gland, which results in insufficient production of thyroid hormones. This deficiency can lead to a slower metabolism and various symptoms like fatigue, weight gain, and depression. The thyroid hormones play a crucial role in regulating metabolic processes, highlighting the significance of this condition in the context of hormonal control and metabolic regulation.
Iodine Deficiency: Iodine deficiency occurs when there is insufficient iodine in the diet, leading to a range of health problems, particularly affecting the thyroid gland. This deficiency disrupts the synthesis of thyroid hormones, which are crucial for regulating metabolism, growth, and development. Without adequate iodine, the body cannot produce enough thyroxine (T4) and triiodothyronine (T3), leading to metabolic issues and other complications.
Liquid Chromatography: Liquid chromatography is a powerful analytical technique used to separate, identify, and quantify components in a mixture by passing it through a stationary phase while using a liquid mobile phase. This method is widely used in various fields, including biochemistry and pharmaceutical analysis, as it allows for the precise analysis of complex biological samples, such as hormones. Understanding how liquid chromatography works is crucial for exploring metabolic regulation mechanisms, particularly in the context of thyroid hormones and their impact on metabolism.
Metabolism: Metabolism refers to the sum of all chemical reactions that occur within a living organism, enabling it to maintain life. These reactions are crucial for converting food into energy, building cellular structures, and regulating bodily functions. Metabolism is divided into two main categories: catabolism, which breaks down molecules to release energy, and anabolism, which uses energy to construct components of cells like proteins and nucleic acids. Hormones play a significant role in regulating metabolic pathways, influencing how efficiently our bodies utilize energy.
Negative feedback: Negative feedback is a regulatory mechanism in biological systems where a change in a variable triggers a response that counteracts the initial change, thus maintaining homeostasis. This process is crucial for ensuring that physiological systems operate within optimal ranges, and it plays a key role in hormonal control of metabolism and regulation of thyroid hormones, which help balance energy levels and metabolic processes in the body.
Neurological effects: Neurological effects refer to the impact that substances, conditions, or hormonal changes have on the nervous system, including brain function, nerve signaling, and overall neurological health. These effects can influence behavior, cognition, and physical coordination, highlighting the intricate relationship between hormones, metabolism, and nervous system functionality.
Radioimmunoassay: Radioimmunoassay is a sensitive laboratory technique used to measure the concentration of antigens, such as hormones, in a sample by using radioactively labeled antibodies. This method combines the specificity of immunology with the precision of radioactivity detection, making it especially useful for quantifying low levels of substances in biological samples, such as thyroid hormones involved in metabolic regulation.
Selenium: Selenium is a trace element that is essential for human health, playing a crucial role in the function of various enzymes and proteins, particularly those involved in antioxidant defense and thyroid hormone metabolism. Its significance extends to the regulation of thyroid hormones, which are vital for metabolic processes in the body. Selenium is incorporated into selenoproteins, which help protect cells from oxidative damage and support the conversion of inactive thyroid hormone (T4) to its active form (T3).
Signal Transduction: Signal transduction is the process by which cells convert external signals into a functional response. This involves a series of molecular events, typically initiated by the binding of signaling molecules to specific receptors on the cell surface, leading to changes in cellular activities such as metabolism, gene expression, or cell division.
Thermogenesis: Thermogenesis is the process by which the body generates heat, particularly through metabolic activity. This process plays a critical role in maintaining body temperature and energy balance, especially in response to various physiological states such as cold exposure and overfeeding. Thyroid hormones significantly influence thermogenesis by regulating metabolic rates and stimulating energy expenditure in tissues like brown adipose tissue.
Thyroid peroxidase: Thyroid peroxidase (TPO) is an enzyme located in the thyroid gland that plays a critical role in the synthesis of thyroid hormones by catalyzing the iodination of tyrosine residues in thyroglobulin. This process is essential for the production of thyroxine (T4) and triiodothyronine (T3), which are crucial regulators of metabolic processes in the body. TPO's activity is vital for normal thyroid function and metabolic regulation, as it directly impacts hormone levels that control metabolism, energy production, and overall physiological balance.
Thyroxine: Thyroxine, also known as T4, is a hormone produced by the thyroid gland that plays a vital role in regulating metabolism, growth, and development. It influences almost every cell in the body by increasing the basal metabolic rate, promoting protein synthesis, and stimulating the breakdown of carbohydrates and fats. Thyroxine works closely with another thyroid hormone called triiodothyronine (T3) to maintain metabolic homeostasis and energy balance.
Triiodothyronine: Triiodothyronine, often abbreviated as T3, is a thyroid hormone that plays a crucial role in regulating metabolism, growth, and development in the body. It is derived from thyroxine (T4) and is considered the more active form of thyroid hormone, influencing various physiological processes including heart rate, body temperature, and energy expenditure.