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    Thyroid Hormone Regulation of Metabolism

    Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. ...

    Physiol Rev. 2014 Apr; 94(2): 355–382.

    doi: 10.1152/physrev.00030.2013

    PMCID: PMC4044302 PMID: 24692351

    Thyroid Hormone Regulation of Metabolism

    Rashmi Mullur, Yan-Yun Liu, and Gregory A. Brent

    Author information Copyright and License information Disclaimer

    This article has been cited by other articles in PMC.

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    Abstract

    Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.

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    I. INTRODUCTION

    Thyroid hormone (TH) regulates metabolic processes essential for normal growth and development as well as regulating metabolism in the adult (28, 40, 189). It is well established that thyroid hormone status correlates with body weight and energy expenditure (80, 127, 143). Hyperthyroidism, excess thyroid hormone, promotes a hypermetabolic state characterized by increased resting energy expenditure, weight loss, reduced cholesterol levels, increased lipolysis, and gluconeogenesis (26, 184). Conversely, hypothyroidism, reduced thyroid hormone levels, is associated with hypometabolism characterized by reduced resting energy expenditure, weight gain, increased cholesterol levels, reduced lipolysis, and reduced gluconeogenesis (27). TH stimulates both lipogenesis and lipolysis, although when TH levels are elevated, the net effect is fat loss (191). TH influences key metabolic pathways that control energy balance by regulating energy storage and expenditure (40, 127, 157). TH regulates metabolism primarily through actions in the brain, white fat, brown fat, skeletal muscle, liver, and pancreas.

    A number of recent reviews have focused on specific actions of TH in metabolic regulation (Figure 1, Table 1). These include the molecular mechanisms of TH action (28, 40), lipid regulation (270), cross-talk with nuclear receptors (157), the role of corepressors in metabolic regulation (185), thyroid hormone adrenergic interactions (233), facultative thermogenesis (229), and the metabolic influences on central regulation of TH (117, 163). This review will examine the various sites of TH action and mechanisms that mediate metabolic regulation, focusing on the interaction among the pathways that regulate lipid and carbohydrate metabolism, and the balance of energy storage and energy expenditure. The themes among the interacting TH metabolic pathways include the influence of nutrient feedback, through nuclear receptor crosstalk and epigenetic modifications of histones, the impact of adrenergic signaling, and local ligand availability (Table 2). We will conclude with the application of these common mechanisms to therapeutic targets.

    FIGURE 1.

    Overview of sites of thyroid hormone regulation of metabolism. Hypothalamic-Pituitary-Thyroid axis: thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) respond primarily to circulating serum T4, converted in the hypothalamus and pituitary to T3 by the 5′-deiodinase type 2 (D2). The monocarboxylate transporter 8 (MCT8) is required for T3 transport into the pituitary and hypothalamus. A, parvalbuminergic neurons (PBN): PBN are a population of newly discovered neurons in the anterior hypothalamus that are directly linked to the regulation of cardiovascular function, including heart rate, blood pressure, and body temperature. Thyroid hormone receptor signaling is required for the normal development of PBN neurons linking thyroid hormone to cardiac and temperature regulation. B, paraventricular nucleus of the hypothlamus (VPN): leptin, produced in peripheral fat tissue, provides feedback at the VPN, stimulates signal transducer and activator of transcription (STAT)3 phosphorylation (STAT3-P*), which directly stimulates TRH expression. Leptin also stimulates TRH indirectly in the arcuate nucleus by inhibiting neuropeptide Y and agouti-related protein, stimulating proopiomelanocortin (POMC), and the POMC product α-melanocyte stimulating hormone (α-MSH) stimulates CREB in the TRH neuron (indirect pathway is not shown in Figure 1). C, ventromedial nucleus of the hypothalamus (VMH): hyperthyroidism or T3 treatment stimulates de novo fatty acid synthesis in the VMH, which inhibits AMPK phosphorylation and increases fatty acid synthase (FAS) activity. Increased hypothalamic lipid synthesis is associated with activation of the sympathetic nervous system (SNS) which stimulates brown adipose tissue (BAT). D, BAT: adrenergic signaling through the β3-adrenergic receptor (AR) stimulates UCP1 gene expression, stimulates D2 activity by deubiquitination, and promotes thermogenesis and weight loss. The metabolic signal from bile acid via the G protein-coupled membrane bile acid receptor (TGR5) has been shown in one model to stimulate D2 activity and local T3 production, which further stimulates BAT lipolysis, UCP1 expression, and thermogenesis. E, white adipose tissue (WAT): SNS signals via β1- and β2-AR stimulate WAT lipolysis. T3 stimulates local production of norepinephrine (NE), increasing lipolysis and reducing body fat. F, liver: T3 is involved in both cholesterol and fatty acid metabolism (see details in Figure 3). HOMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; ACC1, acetyl-CoA carboxylase 1; CYP7a1, cytochrome P-450 7A1; CPT-1α, carnitine palmitoyltransferase 1α; LDL-R, low-density lipoprotein receptor. G, muscle: Forkhead box O3 (FoxO3) induces D2 expression, increases local T3 in skeletal muscle, and promotes T3-target gene expression; myoD, myosin heavy chain (MHC) and sarcoplasmic reticulum Ca2+-ATPase (SERCA). Local T3 also determines the relative expression level of MHC and SERCA isoforms. Expression level of these isoforms determines muscle fiber types and initiation of repair. SERCA2a is primarily expressed in slow-twitch fibers and SERCA1 in fast-twitch fibers. T3 stimulates SERCA, which hydrolyzes ATP and increases energy expenditure. H, pancreas: T3 and TR are required for normal pancreatic development and function. In rat pancreatic β cells, expression of TR and D2 are activated during normal development. T3 treatment enhances Mafa (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A) transcription factor gene expression and increases MAFA protein content, the key factor for maturation of β cells to secrete insulin in response to glucose. T3 stimulates cyclin D1 (CD1) gene expression and protein level and promotes proliferation. Increasing cyclin D1 activates the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway.

    Source : www.ncbi.nlm.nih.gov

    A&P II

    Study A&P II- Ch.18 The Heart flashcards. Create flashcards for FREE and quiz yourself with an interactive flipper.

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    BIOL 2402

    A&P II- Ch.18 The Heart

    45cards Aylin T. Biology

    Human Anatomy & Physiology

    Which statement is correct regarding the ventricles?

    The right ventricle empties into the pulmonary trunk

    Consider the following characteristics of the cells found in muscle tissue. Which feature is shared by both cardiac muscle and skeletal muscle?

    Striations

    Blood within the pulmonary veins returns to the ________.

    left atrium

    The __________ valve is located between the right atrium and the right ventricle.

    tricuspid

    Which of the following is the innermost layer of the heart?

    endocardium

    Which of the following structures collects the depolarization wave from the atria to pass it onto the ventricles?

    AV node

    If the vagal nerves to the heart were cut, the result would be that ________.

    the heart rate would increase by about 25 beats per minute

    Which of the following does NOT deliver deoxygenated blood to the heart?

    pulmonary veins

    Name the ridged bundles of muscle found projecting inside the right atrium.

    Pectinate muscles

    Identify the right atrioventricular valve.

    tricuspid valve

    Identfiy the valve located at the exit of the right ventricle.

    Pulmonary semilunar valve

    The moderator band is found on both the right and left side of the heart.

    false

    Oxygenated blood flows through the right side of the heart.

    false

    Which of the following terms is correctly matched to its description?

    quiescent period: total heart relaxation between heartbeats

    The right atrioventricular valve prevents backflow of blood from the right ventricle into the __________.

    right atrium

    Blood enters the left and right coronary arteries directly from which vessel or chamber?

    aorta

    What separates the parietal and visceral pericardium?

    pericardial activity

    Identify the most muscular chamber.

    left ventricle

    Name the inner lining of the heart.

    endocardium

    Identify the valve found between the left atrium and left ventricle.

    Bicuspid (mitral) valve

    What heart chamber pushes blood through the aortic semilunar valve?

    Left ventricle

    Name the needle like ridges of muscle lining the ventricles.

    Trabeculae carneae

    What fibrous structure functions to anchor the atrioventricular valves in a closed position?

    Chordae tendineae

    Blood on the right never mixes with blood on the left, once the heart is fully developed.

    true

    Into which chamber of the heart do the superior vena cava, inferior vena cava, and coronary sinus return deoxygenated blood?

    right atrium

    Which chamber of the heart sends oxygenated blood to the systemic circuit via the aorta?

    left ventricle

    Which layer of the heart wall contracts and is composed primarily of cardiac muscle tissue?

    myocardium

    Why are gap junctions a vital part of the intercellular connection of cardiac muscles?

    Gap junctions allow action potentials to spread to connected cells.

    Which of the following would increase cardiac output?

    epinephrine

    Which statement regarding cardiac muscle structure is accurate?

    Myofibrils of cardiac muscle tissue vary in diameter and branch extensively.

    When released in large quantities, thyroxine, a thyroid gland hormone, causes a sustained increase in heart rate.

    true

    Which of the following would cause a DECREASE in cardiac output (CO)?

    decreasing thyroid function (thyroxine)

    Which of the following increases stroke volume?

    exercise

    What causes heart sounds?

    heart valve closure

    Which of the following descriptions does NOT describe atrioventricular (AV) valves?

    pocket-like

    Which valve is located between the right atrium and ventricle?

    tricuspid valve

    Hemorrhage with a large loss of blood causes ________.

    a lowering of blood pressure due to change in cardiac output

    The role of the chordae tendineae is to open the AV valves at the appropriate time.

    False

    What is the ligamentum arteriosum?

    A remnant of the ductus arteriosus

    Which chamber of the heart exits into the pulmonary trunk?

    right ventricle

    What is the function of the coronary circulation?

    Provide a blood supply to the heart

    Identify the ear like flaps that are attached to the top chambers of the heart.

    auricle

    The base of the heart is located at the bottom of the heart.

    false

    The first branch off the arch of the aorta is the brachiocephalic artery in both the sheep and the human.

    true

    The first heart sound (the "lub" of the "lub-dup") is caused by __________.

    closure of the atrioventricular valves

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    A&P Chapter 18 and 19 True/False Questions Flashcards

    Start studying A&P Chapter 18 and 19 True/False Questions. Learn vocabulary, terms, and more with flashcards, games, and other study tools.

    A&P Chapter 18 and 19 True/False Questions

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    Auricles slightly increase blood volume in the ventricles.

    Click card to see definition 👆

    False

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    If the aorta and pulmonary trunk were switched, oxygen rich blood would be pumped from the left ventricle to the lungs.

    Click card to see definition 👆

    True

    Click again to see term 👆

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    Terms in this set (23)

    Auricles slightly increase blood volume in the ventricles.

    False

    If the aorta and pulmonary trunk were switched, oxygen rich blood would be pumped from the left ventricle to the lungs.

    True

    The myocardium receives its blood supply from the coronary arteries.

    True

    Anastomoses among coronary arterial branches provide collateral routes for blood delivery to the heart muscle.

    True

    Tissues damaged by myocardial infarction are replaced by connective tissue.

    True

    The left side of the heart pumps the same volume of blood as the right.

    True

    Arterial blood supply to heart muscle is continuous whether the heart is in systole or diastole.

    False

    Cardiac muscle has more mitochondria and depends less on a continual supply of oxygen than does skeletal muscle.

    False

    An electrocardiogram (ECG) provides direct information about valve function.

    False

    Autonomic regulation of heart rate is via two reflex centers found in the pons.

    False

    The "lub" sounds of the heart are valuable in diagnosis because they provide information about the function of the heart's pulmonary and aortic semilunar valves.

    False

    When released in large quantities, thyroxine, a thyroid gland hormone, causes a sustained increase in heart rate.

    True

    As pressure in the aorta rises due to atherosclerosis, more ventricular pressure is required to open the aortic valve.

    True

    Congestive heart failure means that the pumping efficiency of the heart is depressed so that there is inadequate delivery of blood to body tissues.

    True

    Arterial pressure in the pulmonary circulation is much higher than in the systemic circulation because of its proximity to the heart.

    False

    The thick-walled arteries close to the heart are called muscular arteries.

    False

    Hypotension is generally considered systolic blood pressure that is below 100 mm Hg.

    True

    The carotid sinus reflex protects the blood supply to the brain, whereas the aortic reflex is more concerned with maintaining adequate blood pressure in the systemic circuit as a whole.

    True

    A precapillary sphincter is a cuff of smooth muscle that regulates the flow of blood into the capillaries.

    True

    The outermost layer of a blood vessel is the tunica intima.

    False

    The adjustment of blood flow to each tissue in proportion to its requirements at any point in time is termed autoregulation.

    True

    Vasodilation is a widening of the lumen due to smooth muscle contraction.

    False

    The cerebral arterial circle (circle of Willis) is an arterial anastomosis.

    True

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    Verified questions

    ANATOMY AND PHYSIOLOGY

    In comparing a parallel artery and vein, you would find that a. the artery wall is thicker. b. the artery diameter is greater. c. the artery lumen is smaller. d. the artery endothelium is thicker.

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    Hannah, a 14-year-old girl undergoing a physical examination before being admitted to summer camp, was found to have a loud heart murmur at the second intercostal space on the left side of the sternum. The murmur takes the form of a swishing sound with no high-pitched whistle. What, exactly, is producing the murmur?

    Verified answer

    ANATOMY AND PHYSIOLOGY

    People who are deaf due to cochlear damage do not suffer motion sickness. Why not?

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