Thyroid hormones and lipid metabolism

Some major pathways of lipid metabolism are under control of thyroid hormones. Thyroxine changes the lipid composition of different cell membranes. Modification of thyroid hormone metabolism during ontogenesis is one of the reasons of changes in lipid composition and function of cell nuclei and its other structures. Atherosclerosis and obesity may be a result of the thyroid dysfunction and modulation of the cellular lipid metabolism.     

Thyroid hormones and muscle phenotype: involvement of new signaling pathways

Thyroid hormones (TH) are known to control development, body and muscle growth, as well as to determine muscle phenotype in the adult. TH affect muscle properties through nuclear receptors; they act either by a positive or a negative control on target genes that encode proteins accounting for contractile or metabolic phenotypes. Contractile activity and muscle load also affect muscle phenotype; several intracellular signaling pathways are involved in the transduction of signals related to contractile activity, including the calcineurin/NFAT pathway. Calcineurin activity is negatively controlled by MCIP-1 protein (modulatory calcineurin-interacting protein-1). We recently performed an experiment aimed at examining the specific and combined effects of the pharmacological calcineurin inhibition (using cyclosporin-A CsA administration) and thyroid hormone deficiency. The expected effects of CsA administration were only observed if TH were available, while thyroid deficiency totally blunted the muscle responses to calcineurin inhibition. In conditions of thyroid hormone deficiency, there was no response to the pharmacological inhibition of calcineurin, usually known to induce a slow-to-fast IIA transition associated with an enhancement of mitochondrial biogenesis in normothyroid rats. Moreover, thyroid deficiency markedly decreased the expression of MCIP-1 and MCIP-2 mRNA and proteins, two endogenous calcineurin inhibitors; such results clearly suggest that thyroid hormone and calcineurin pathways are interconnected.     

Thyroid hormones in cyclostomes and fish and their role in regulation of intermediary metabolism

1. Experimental data obtained in cyclostomes and fish concerning the plasma levels of thyroxine and tri-iodothyronine as well as their influence on intermediary metabolism of lipids, carbohydrates, and proteins are reviewed. 2. The information dealing with the physiological role of thyroid hormones in regulation of metabolic processes seems to be scarce in cyclostomes and controversial in fishes. 3. Nevertheless, the data covered in the review support the generalization that thyroid hormones, probably along with some other hormones, exert a regulatory action on the metabolic processes already on the lower stage of the evolution of poikilothermic vertebrates.     

Thyroid hormones and mitochondria

Because of their central role in the regulation of energy-transduction, mitochondria, the major site of oxidative processes within the cell, are considered a likely subcellular target for the action that thyroid hormones exert on energy metabolism. However, the mechanism underlying the regulation of basal metabolic rate (BMR) by thyroid hormones still remains unclear. It has been suggested that these hormones might uncouple substrate oxidation from ATP synthesis, but there are no clear-cut data to support this idea. Two iodothyronines have been identified as effectors of the actions of thyroid hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2). Both have significant effects on BMR, but their mechanisms of action are not identical. T3 acts on the nucleus to influence the expression of genes involved in the regulation of cellular metabolism and mitochondria function; 3,5-T2, on the other hand, acts by directly influencing the mitochondrial energy-transduction apparatus. A molecular determinant of the effects of T3 could be uncoupling protein-3 (UCP-3), while the cytochrome-c oxidase complex is a possible target for 3,5-T2. In conclusion, it is likely that iodothyronines regulate energy metabolism by both short-term and long-term mechanisms, and that they act in more than one way in affecting mitochondrial functions.     

Low muscle and liver glycogen contents in dogs treated with thyroid hormones

Muscle biopsies for glycogen determinations were taken from dogs before (controls) and after prolonged treatment with thyroid hormones (T4 or T3). The glycogen content in quadriceps femoris was measured before exercise, immediately after its cessation, and during 24h of post-exercise recovery. The effect of thyroxine treatment on the liver glycogen content both at rest and following physical effort was also studied. A marked decrease in the muscle glycogen content determined at rest was found both in T4 and T3-treated dogs in comparison with controls. Physical exercise diminished the muscle glycogen store to similar values in control and thyroid hormone-treated dogs, but the rate of the muscle glycogen utilization during exercise was lower in the latter. The rate of the post-exercise muscle glycogen synthesis was considerably inhibited in thyroid hormone-treated dogs, but 1 hr glucose infusion, applied immediately after cessation of exercise, accelerated the rate of glycogen re-synthesis, so it was close to that in controls without infusion. Thyroxine treatment also affected the liver glycogen store. Both at rest and after physical exercise significantly lower liver glycogen contents were found in T4-treated dogs than in controls.     

Thyroid hormones regulate lipid metabolism in a teleost Anabas testudineus (Bloch)

We compared the long-term action of 3,5,3′-triiodo-l-thyronine (T₃) and 3,5-diiodo-l-thyronine (T₂) on lipid metabolism in a teleost Anabas testudineus. Among the six groups of animals used in this experiment, except for the control group, all received 6-propylthiouracil (6-PTU) to create a hypothyroid state in order to analyse the action of iodothyronines on lipid metabolism. Injections of 6-PTU reduced T₃ concentration in the circulation by 79.6% and injections of iodothyronines enhanced the level of T₃ in the plasma, and a maximum increase was observed in T₃ (500 ng)-treated specimens. Analysis of lipogenic enzymes in liver and heart showed that a tissue-specific variation exists in the action of thyroid hormones and, in many cases, activity is higher in T₂-treated groups. Analysis of various lipid classes showed that long-term administration of T₂ is also effective in producing a comparable effect with that of T₃ on lipid metabolism.     

Thyroid hormones and the cardiomyocytes

The authors present the current knowledge on the intracellular mechanisms of thyroid hormone action in the cardiomyocytes. Many of the clinical manifestations of thyroid diseases are due to the ability of thyroid hormone to alter cardiovascular hemodynamics. Triiodothyronine affects the hemodynamic state mainly by its influence on the expression of cardiomyocyte genes. These genes encode both structural and regulatory proteins in the heart (myosin heavy chains, sarcoplasmic reticulum calcium-activated ATP-ase, phospholamban). The impaired myocardium contractile activity in hypothyreosis reminds findings in heart failure and may warrant further exploration of therapeutic approaches using thyroid hormone to improve cardiac function in heart failure.     

Thyroid hormones control lipid composition and membrane fluidity of skeletal muscle sarcolemma.

Sarcolemma membrane lipid phase of skeletal muscles of hyperthyroid animals was compared to that of control (euthyroid) ones. Hyperthyroidism caused 15% decrease in cholesterol and 70% increase in the phospholipid content of the membrane. This was accompanied by the alterations in proportions between individual phospholipid classes, and was followed by changes in the composition of phospholipid fatty acids. The calculated fatty acid unsaturation index was higher for membrane lipid phase of hyperthyroid animals than of euthyroid ones. Thyroxine-induced alterations in the lipid composition of sarcolemma caused changes in the membrane fluidity and the activity of calmodulin-stimulated (Ca(2+)-Mg(2+)-ATPase. Measurements of the steady-state fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene indicated that the lipid phase transition of membrane vesicles occurred at 25.9 degrees C and at 28.9 degrees C for preparations isolated from hyperthyroid and euthyroid rabbits, respectively. Arrhenius plot break-point temperature for CaM-stimulated (Ca(2+)-Mg(2+)-ATPase activity was lower in membrane preparations isolated from hyperthyroid (26.9 degrees C) than from euthyroid ones (30.0 degrees C). Thus, the increase of the membrane fluidity presumably caused that the enzyme was characterized by the lower activation energy value. This phenomenon may be viewed as a supplementary mechanism for activation of the enzyme by thyroid hormones to previously reported elevation of the amount of (Ca(2+)-Mg(2+)-ATPase protein exerted by hyperthyroidism (Famulski et al. (1988) Eur. J. Biochem., 171, 363-368; Famulski and Wrzosek (1988) in The Ion Pumps-Structure, Function and Regulation (Stein, W.D., ed.), pp. 355-360, Alan R. Liss, New York).     

Thyroid hormones, learning and memory

Thyroid hormones (THs), T3 and T4, have many physiological actions and are essential for normal behavioral, intellectual and neurological development. THs have a broad spectrum of effects on the developing brain and mediate important effects within the CNS throughout life. Insufficient maternal iodine intake during gestation and TH deficiency during human development are associated to pathological alterations such as cretinism and mental retardation. In adulthood, thyroid dysfunction is related to neurological and behavioral abnormalities, including memory impairment. Analysis of different experimental models suggests that most of the effects on cognition as a result of thyroid dysfunction rely on hippocampal modifications. Insufficiency of THs during development thus alters hippocampal synaptic function and impairs behavioral performance of hippocampal-dependent learning and memory tasks that persist in euthyroid adult animals. In the present review, we summarize the current knowledge obtained by clinical observations and experimental models that shows the importance of THs in learning and mnemonic processes.     

Thyroid hormones and adipose tissue development

The effect of thyroid hormones on the cellularity of the retroperitoneal adipose tissue (R.P.A.T.) was investigated in rats that were 3, 6 and 12 weeks old. Two groups of rats were respectively made hypothyroid by the antithyroid compound propylthiouracil, or hyperthyroid by thyroxine. The number of adipocytes was less in the hypothyroid rats than in the controls; it was higher in the hyperthyroid rats without any concomitant increase in the weight of their R.P.A.T. Moreover, there was no significant correlation between adipose cell number and adipose tissue weight within any group of T4 or control rats. In all groups of rats, the number of adipose cells in the R.P.A.T. was larger in males than in females; the difference was highly significant in 12 week old control rats.     

Thyroid hormones in chronic heat exposed men

Previous reports have indicated that thyroid gland activity, is depressed in the heat. Total thyroxine (T₄) and triiodothyronine (T₃) serum levels in 17 workers of the metal work shop at a plant near the Dead Sea and 8 workers in Beer Sheva, Israel were examined. The metal workshop of the plant near the Dead Sea is part of a large chemical plant. The one in Beer Sheva is part of a large construction company. Maintenance work, as well as metal work projects are performed in both workshops. During the work shifts, the workers of the Dead Sea plant were exposed to temperatures ranging from 30–36°C (May–Oct.) and 14–21°C (Dec.–Feb). In Beer Sheva the range was 25–32°C (June–Sept.) and 10– 17°C (Dec.–Feb.). Total T₄ was measured by competitive protein binding and total T₃ by radioimmunoassay in blood drawn before work (0700) in July and January. In summer. T₄ was higher and T₃ was lower for both groups than in winter. The observed summer T₃ decrease may result from depressed extrathyroidal conversion of T₄ to T₃. We conclude that the regulation of energy metabolism in hot climates may be related to extrathyroidal conversion of T₄ to T₃.This study was part of A. Gertner's Ph.D. Research Dissertation     

Thyroid hormones and phospholipase activity in rat liver mitochondria

The rate of the hydrolysis of mitochondrial phospholipids isolated from the liver of rats given excess amount of thyroid hormones for a long time was higher than in normal animals. Activation of this process determined by endogenous phospholipase of mitochondria could be also observed in liver mitochondria isolated 2 days after a single injection of L-thyroxine into rats. It is assumed that the hyperthyrosis-induced acceleration of lipid peroxidation in these organelles might be one of the reasons for activation of endogenous phospholipase of mitochondria.     

Thyroid hormones increase liver and muscle thermogenic capacity in the little buntings (Emberiza pusilla)

Thyroid hormones can increase energy expenditure and stimulate basal thermogenesis by lowering metabolic efficiency. In the present study, we examined the effects of thyroid hormones on basal heat production as well as on several physiological and biochemical measures indicative of thermogenic capacity to test our hypothesis that thyroid hormones stimulate increases in thermogenesis in little buntings. Little buntings that fed on thyroxine (T₄)–laced poultry food of 3 and 5 ppm concentrations showed increases in basal metabolic rate (BMR) during the 3-week acclimation. At the end, these buntings had lower body weights, higher levels of contents of mitochondrial protein, state 4 respiration and cytochrome c oxidase activity in liver and muscle, and higher concentrations of serum triiodothyronine (T₃) and T₄ compared to control buntings. These results support the argument that thyroid hormones play an important role in the regulation of thermogenic ability in buntings by stimulating mitochondrial respiration and enzyme activities associated with aerobic metabolism.     

Thyroid hormones regulate anxiety in the male mouse

Thyroid hormone levels are implicated in mood disorders in the adult human but the mechanisms remain unclear partly because, in rodent models, more attention has been paid to the consequences of perinatal hypo and hyperthyroidism. Thyroid hormones act via the thyroid hormone receptor (TR) α and β isoforms, both of which are expressed in the limbic system. TR's modulate gene expression via both unliganded and liganded actions. Though the thyroid hormone receptor (TR) knockouts and a transgenic TRα1 knock-in mouse have provided us valuable insight into behavioral phenotypes such as anxiety and depression, it is not clear if this is because of the loss of unliganded actions or liganded actions of the receptor or due to locomotor deficits. We used a hypothyroid mouse model and supplementation with tri-iodothyronine (T3) or thyroxine (T4) to investigate the consequences of dysthyroid hormone levels on behaviors that denote anxiety. Our data from the open field and the light–dark transition tests suggest that adult onset hypothyroidism in male mice produces a mild anxiogenic effect that is possibly due to unliganded receptor actions. T3 or T4 supplementation reverses this phenotype and euthyroid animals show anxiety that is intermediate between the hypothyroid and thyroid hormone supplemented groups. In addition, T3 but not T4 supplemented animals have lower spine density in the CA1 region of the hippocampus and in the central amygdala suggesting that T3-mediated rescue of the hypothyroid state might be due to lower neuronal excitability in the limbic circuit.