gc-1-compound and Hypothyroidism

Thyromimetics represent a class of experimental drugs that can stimulate tissue-selective thyroid hormone action. As such, thyromimetics should have effects on the hypothalamic-pituitary-thyroid (HPT) axis, but details of this action and the subsequent effects on systemic thyroid hormone levels have not been reported to date. Here, we compare the HPT-axis effects of sobetirome, a well-studied thyromimetic, with Sob-AM2, a newly developed prodrug of sobetirome that targets sobetirome distribution to the central nervous system (CNS). Similar to endogenous thyroid hormone, administration of sobetirome and Sob-AM2 suppress HPT-axis gene transcript levels in a manner that correlates to their specific tissue distribution properties (periphery vs CNS, respectively). Dosing male C57BL/6 mice with sobetirome and Sob-AM2 at concentrations ≥10 μg/kg/d for 29 days induces a state similar to central hypothyroidism characterized by depleted circulating T4 and T3 and normal TSH levels. However, despite the systemic T4 and T3 depletion, the sobetirome- and Sob-AM2-treated mice do not show signs of hypothyroidism, which may result from the presence of the thyromimetic in the thyroid hormone-depleted background.

Topics: Acetates; Animals; Central Nervous System; Hypothalamo-Hypophyseal System; Hypothyroidism; Male; Mice; Mice, Inbred C57BL; Phenols; Pituitary Gland; Radioimmunoassay; Thyroid Gland; Thyroid Hormones; Thyroxine; Triiodothyronine

Investigate the effect of GC-1 on tolerance to exercise in rats with experimental hypothyroidism.. Hypothyroidism was induced with methimazole sodium and perchlorate treatment. Six groups with eight animals were studied: control group (C), hypothyroid group without treatment (HYPO); hypothyroidism treated with physiological doses of tetraiodothyronine (T4) or 10 times higher (10×T4); hypothyroidism treated with equal molar doses of GC-1 (GC-1) or 10 times higher (10×GC-1). After eight weeks, each animal underwent an exercise tolerance test by measuring the time (seconds), in which the rats were swimming with a load attached to their tails without being submerging for more than 10 sec. After the test, the animals were killed, and blood samples were collected for biochemical analysis, and the heart and soleus muscle were removed for weighing and morphometric analysis of the cardiomyocyte.. Hypothyroidism significantly reduced tolerance to exercise and, treatment with GC-1 1× or T4 in physiological doses recover tolerance test to normal parameters. However, high doses of T4 also decreased tolerance to physical exercise. Conversely, ten times higher doses of GC-1 did not impair tolerance to exercise. Interestingly, hypothyroidism, treated or not with T4 in a physiological range, GC-1 or even high doses of GC-1 (10X) did not change cardiomyocyte diameters and relative weight of the soleus muscle. In contrast, higher doses of T4 significantly increased cardiomyocyte diameter and induced atrophy of the soleus muscle.. Unlike T4, GC-1 in high doses did not modify tolerance to physical exercise in the rats with hypothyroidism.

Topics: Acetates; Animals; Exercise Tolerance; Hypothyroidism; Methimazole; Muscle, Skeletal; Myocytes, Cardiac; Perchlorates; Phenols; Rats, Wistar; Sodium Compounds; Swimming; Thyroid Hormone Receptors beta; Thyrotropin; Thyroxine; Triiodothyronine

Thyroid hormones have important actions in the developing central nervous system. We describe here a novel action of thyroid hormone and its nuclear receptors on maturation of cerebellar gamma-aminobutyric acid (GABA)-ergic interneurons from their precursor cells. In rats, the density of GABAergic terminals in the cerebellum was decreased by hypothyroidism, as shown by immunohistochemistry for the GABA transporter GAT-1. This was due, at least partially, to a decreased number of GABAergic cells, because the number of Golgi II cells in the internal granular layer was decreased. GABAergic interneurons in the cerebellum differentiate from precursors expressing the Pax-2 transcription factor, generated in the subventricular zone of the embryonic fourth ventricle from where they migrate to the cerebellum. Hypothyroidism caused both decreased proliferation and delayed differentiation of precursors, with the net effect being an accumulation of immature cells during the neonatal period. The contribution of thyroid hormone receptors was studied by treating hypothyroid rats with T(3) or with the thyroid hormone receptor (TR) beta-selective agonist GC-1. Whereas treatment with T(3) reduced the number of precursors to control levels, GC-1 had only a partial effect, indicating that both TRalpha1 and TRbeta mediate the actions of T(3). Deletion of TRalpha1 in mice decreased cerebellar GAT-1 expression and Pax-2 precursor cell proliferation. It is concluded that thyroid hormone, acting through the nuclear receptors, has a major role in the proliferation and further differentiation of the Pax-2 precursors of cerebellar GABAergic cells.

Topics: Acetates; Age Factors; Animals; Blotting, Western; Cell Differentiation; Cell Proliferation; Cerebellum; GABA Plasma Membrane Transport Proteins; gamma-Aminobutyric Acid; Hypothyroidism; Immunohistochemistry; Interneurons; Ki-67 Antigen; Mice; Mice, Inbred BALB C; PAX2 Transcription Factor; Phenols; Rats; Rats, Wistar; Receptors, Thyroid Hormone; Thyroid Hormones

We investigated the effects of GC-1, a TRbeta-selective thyromimetic, on bone development of hypothyroid rats. Whereas T3 reverted the IGF-I deficiency and the skeletal defects caused by hypothyroidism, GC-1 had no effect on serum IGF-I or on IGF-I protein expression in the epiphyseal growth plate of the femur, but induced selective effects on bone development. Our findings indicate that T3 exerts some essential effects on bone development that are mediated by TRbeta1.. We investigated the role of the thyroid hormone receptor beta1 (TRbeta1) on skeletal development of rats using the TRbeta-selective agonist GC-1.. Twenty-one-day-old female rats (n = 6/group) were rendered hypothyroid (Hypo) and treated for 5 weeks with 0.3 ug/100 g BW/day of T3 (1xT3), 5xT3, or equimolar doses of GC-1 (1xGC-1 and 5xGC-1). Serum triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF)-I concentrations were determined by radioimmunoassay (RIA). BMD and longitudinal bone growth were determined by DXA. Trabecular bone histomorphometry and epiphyseal growth plate (EGP) morphometry were performed in the distal femur. Expressions of IGF-I protein and of collagen II and X mRNA were evaluated by immunohistochemistry and in situ hybridization, respectively. To determine hormonal effects on ossification, skeletal preparations of hypothyroid-, 5xGC-1-, and 5xT3-treated neonatal rats were compared.. Hypothyroidism impaired longitudinal body growth and BMD gain, delayed ossification, reduced the number of hypertrophic chondrocytes (HCs; 72% versus Euthyroid [Eut] rats; p < 0.001), and resulted in disorganized columns of EGP chondrocytes. Serum IGF-I was 67% reduced versus Eut rats (p < 0.001), and the expression of IGF-I protein and collagen II and X mRNA were undetectable in the EGP of Hypo rats. T3 completely or partially normalized all these parameters. In contrast, GC-1 did not influence serum concentrations or EGP expression of IGF-I, failed to reverse the disorganization of proliferating chondrocyte columns, and barely affected longitudinal growth. Nevertheless, GC-1 induced ossification, HC differentiation, and collagen II and X mRNA expression and increased EGP thickness to Eut values. GC-1-treated rats had higher BMD gain in the total tibia, total femur, and in the femoral diaphysis than Hypo animals (p < 0.05). These changes were associated with increased trabecular volume (48%, p < 0.01), mineralization apposition rate (2.3-fold, p < 0.05), mineralizing surface (4.3-fold, p < 0.01), and bone formation rate (10-fold, p < 0.01).. Treatment of hypothyroid rats with the TRbeta-specific agonist GC-1 partially reverts the skeletal development and maturation defects resultant of hypothyroidism. This finding suggests that TRbeta1 has an important role in bone development.

Topics: Absorptiometry, Photon; Acetates; Animals; Body Size; Bone and Bones; Bone Density; Bone Development; Cell Differentiation; Chondrocytes; Collagen Type II; Collagen Type X; Female; Growth Plate; Humans; Hypothyroidism; Immunohistochemistry; In Situ Hybridization; Insulin-Like Growth Factor I; Osteogenesis; Phenols; Radioimmunoassay; Rats; Rats, Wistar; Receptors, Thyroid Hormone; RNA, Messenger; Thyroid Hormone Receptors beta; Time Factors

In newborns and small mammals, cold-induced adaptive (or nonshivering) thermogenesis is produced primarily in brown adipose tissue (BAT). Heat production is stimulated by the sympathetic nervous system, but it has an absolute requirement for thyroid hormone. We used the thyroid hormone receptor-beta--selective (TR-beta--selective) ligand, GC-1, to determine by a pharmacological approach whether adaptive thermogenesis was TR isoform--specific. Hypothyroid mice were treated for 10 days with varying doses of T3 or GC-1. The level of uncoupling protein 1 (UCP1), the key thermogenic protein in BAT, was restored by either T3 or GC-1 treatment. However, whereas interscapular BAT in T3-treated mice showed a 3.0 degrees C elevation upon infusion of norepinephrine, indicating normal thermogenesis, the temperature did not increase (<0.5 degrees C) in GC-1--treated mice. When exposed to cold (4 degrees C), GC-1--treated mice also failed to maintain core body temperature and had reduced stimulation of BAT UCP1 mRNA, indicating impaired adrenergic responsiveness. Brown adipocytes isolated from hypothyroid mice replaced with T3, but not from those replaced with GC-1, had normal cAMP production in response to adrenergic stimulation in vitro. We conclude that two distinct thyroid-dependent pathways, stimulation of UCP1 and augmentation of adrenergic responsiveness, are mediated by different TR isoforms in the same tissue.

Topics: Acetates; Adaptation, Physiological; Adipocytes; Adipose Tissue, Brown; Animals; Carrier Proteins; Cold Temperature; Cyclic AMP; Gene Expression Regulation; Glycerolphosphate Dehydrogenase; Heart Rate; Humans; Hypothyroidism; Ion Channels; Liver; Malate Dehydrogenase; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Proteins; Norepinephrine; Phenols; Protein Isoforms; Rats; Receptors, Thyroid Hormone; Sympathetic Nervous System; Thermogenesis; Thyroid Hormones; Triiodothyronine; Uncoupling Protein 1

Thyroid hormones influence the function of many organs and mediate their diverse actions through two types of thyroid hormone receptors, TRalpha and TRbeta. Little is known about effects of ligands that preferentially interact with the two different TR subtypes. In the current study the comparison of the effects of the novel synthetic TRbeta-selective compound GC-1 with T3 at equimolar doses in hypothyroid mice revealed that GC-1 had better triglyceride-lowering and similar cholesterol-lowering effects than T3. T3, but not GC-1, increased heart rate and elevated messenger RNA levels coding for the I(f) channel (HCN2), a cardiac pacemaker that was decreased in hypothyroid mice. T3 had a larger positive inotropic effect than GC-1. T3, but not GC-1, normalized heart and body weights and messenger RNAs of myosin heavy chain alpha and beta and the sarcoplasmic reticulum adenosine triphosphatase (Serca2). Additional dose-response studies in hypercholesteremic rats confirmed the preferential effect of GC-1 on TRbeta-mediated parameters by showing a much higher potency to influence cholesterol and TSH than heart rate. The preferred accumulation of GC-1 in the liver vs. the heart probably also contributes to its marked lipid-lowering effect vs. the absent effect on heart rate. These data indicate that GC-1 could represent a prototype for new drugs for the treatment of high lipid levels or obesity.

Topics: Acetates; Animals; Blotting, Northern; Body Weight; Dose-Response Relationship, Drug; Heart; Hemodynamics; Hypercholesterolemia; Hypolipidemic Agents; Hypothyroidism; Lipids; Male; Mice; Organ Size; Phenols; Rats; Rats, Sprague-Dawley; Receptors, Thyroid Hormone; RNA, Messenger; Thyroxine; Triiodothyronine