Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020672 (hypothermia)
 17,327 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A role for mitochondrial glycerol-3-phosphate dehydrogenase (mGPD) in thermogenesis was investigated in transgenic mice lacking the mGPD gene (mGPD-/-). Reared and studied at 22 C, these mice have a small, but significant, reduction (7-10%) in energy expenditure, as evidenced by oxygen consumption (QO2) and food intake, and show signs of increased brown adipose tissue (BAT) stimulation, higher plasma T4 and T3 concentrations, as well as increased uncoupling protein 3 (UCP3) expression in muscle. When acclimated at thermoneutrality temperature (32 C), QO2 decreased in both genotypes, but the difference between them widened to 16%, whereas BAT underwent atrophy, and plasma T4 and T3 levels and UCP3 mRNA decreased, yet T3 and UCP3 persisted at significantly higher levels in mGPD-/- mice. Such differences disappeared when the mice were rendered hypothyroid. A compensatory role for the observed changes in BAT, thyroid hormone levels, and UCP3 was investigated with a 2-h cold challenge of 12 C in euthyroid and hypothyroid mice. No hypothermia ensued if the mice had been acclimated at 22 C, but when acclimated at 32 C, euthyroid mGPD-/- mice became significantly more hypothermic than the wild-type controls. When rendered hypothyroid, this difference was accentuated, and the mGPD-/- mice developed profound hypothermia ( approximately 28 vs. 34 C in wild-type mice; P < 0.001). Thus, mGPD-deficient mice have, despite increased plasma T4 and T3, a small, but distinct, reduction in obligatory thermogenesis, which is compensated by increased BAT facultative thermogenesis and by thyroid hormone-dependent mechanisms using other proteins, possibly UCP3. The results support a role for mGPD in thyroid hormone thermogenesis.
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PMID:Evidence for a compensated thermogenic defect in transgenic mice lacking the mitochondrial glycerol-3-phosphate dehydrogenase gene. 1296 27

Thyroxine (T(4)) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology. T(3)-modulated transcription of target genes via activation of TR alpha and TR beta is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure. Here we report the discovery of 3-iodothyronamine (T(1)AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein-coupled trace amine receptor TAR1. Administering T(1)AM in vivo induces profound hypothermia and bradycardia within minutes. T(1)AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH.
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PMID:3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. 1517 Feb 1

As the indicators of sympathetic nervous system (SNS) function, the activity of serum dopamine-beta-hydroxylase (DBH) and interscapular brown adipose tissue (IBAT) monoamine oxidase (MAO) were examined in rats that were chemically thyroidectomized (TX), treated with thyroid hormones, and exposed to cold (4 degrees C). In TX animals, body temperature (bt) significantly decreased, and relative IBAT mass increased as compared with control, euthyroid animals, independent of the ambient temperature. The bt fall in TX cold-exposed animals was more severe, provoking hypothermia after 4 h. Under the same experimental conditions, the SNS function was enhanced as judged by the increased serum DBH and IBAT MAO activities. The treatment of TX animals with T(4) and T(3) re-established the temperature (bt was at the level of controls) and sympathetic homeostasis (DBH activity was at the level of controls) in animals maintained at room temperature but not in those kept under cold conditions. T(4) and T(3) did not affect IBAT MAO activity of TX rats: It remained significantly above the control values whether the animals were maintained at room temperature or exposed to cold. In conclusion, the IBAT of TX cold-exposed rats is incapable of responding to the enhanced thermogenic needs despite the increased SNS activity and thyroid hormone substitution.
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PMID:Effect of cold exposure on serum DBH and interscapular brown adipose tissue MAO activity in hypothyroid T3- and T4-treated rats. 1524 Mar 71

Here, we determined the extent of hypothalamic-pituitary-thyroid (HPT) axis and uncoupling protein-3 (UCP3) involvement in methamphetamine (METH)-induced hyperthermia. Sprague-Dawley rats treated with METH (40mg/kg, s.c.) responded with a hyperthermic response that peaked 1h post-treatment and was sustained through 2h. After METH treatment, thyroparathyroidectomized (TX) animals developed hypothermia that was sustained for the 3h monitoring period. In TX animals supplemented for 5 days with levothyroxine (100microg/kg, s.c.), METH-induced hypothermia was eliminated and the hyperthermic response was restored. Thyroid hormone levels (T3 and T4), measured in euthyroid animals 1h after METH, remained unchanged. As seen in rats, 1h post-METH (20mg/kg, i.p.) treatment, wild-type (WT) mice developed profound hyperthermia that was sustained for 2h. In marked contrast, UCP3-/- animals developed a markedly blunted hyperthermic response at 1h compared to WT animals. Furthermore, UCP3-/- mice could not sustain this slight elevation in temperature. Two hours post-METH treatment, UCP3-/- animal temperature returned to baseline temperatures. UCP3-/- mice were also completely protected against the lethal effects of METH, whereas 40% of WT mice succumbed to the hyperthermia. These findings suggest that thyroid hormone plays a permissive role in the thermogenic effects induced by METH. Furthermore, the findings indicate that UCP3 plays a major role in the development and maintenance of the hyperthermia induced by METH. The relationship of these results to the hyperthermia induced by 3,4-methylenedioxymethamphetamine (MDMA) is also discussed.
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PMID:UCP3 and thyroid hormone involvement in methamphetamine-induced hyperthermia. 1534 23

1. The present study was carried out to explain the resistance of rats injected subcutaneously with risperidone, the atypical antipsychotic drug, for 21 consecutive days at 0.1 mg/kg per day (a dose equivalent to the one used for patients) to result in an excessive bodyweight despite the increase in diet-uptake in rats against risperidone-induced decrease in body temperature. 2. Rectal temperature measurements were made in 8-week-old male Sprague-Dawley rats maintained under standard laboratory conditions using a 12 h daylight cycle. A s.c. injection of risperidone (0.05 mg/kg) produced hypothermia in rats, which was observed during the daily injection for 21 consecutive days. 3. Sera, white and brown adipose tissues, skeletal muscle and liver were extracted from 8-week-old male Sprague-Dawley rats injected subcutaneously with risperidone (0.01 or 0.1 mg/kg per day) or a vehicle for 21 consecutive days. Serum levels of lipids, ketones and thyroid hormone were measured. The mRNA expression levels in these tissues and organs of the genes encoding the substances involved in heat production and/or lipid metabolism were investigated by using quantitative real-time polymerase chain reaction amplification. 4. Serum nonesterified fatty acid levels in risperidone 0.1 mg/kg per day s.c. injected rats were significantly lower than those in vehicle-injected ones. Serum beta-hydroxybutyrate levels in risperidone-injected rats tended to decrease compared with those in vehicle-injected ones. The serum level of neither triiodothyronine nor thyroxine was affected by risperidone s.c. injection at the doses examined, although their values were within normal limits. 5. Risperidone injection (0.1 mg/kg per day) for 21 consecutive days upregulated mRNA expressions in white adipose tissue of uncoupling protein 3 which dissipates energy as heat; peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha which activates mitochondrial biogenesis to expand the oxidative machinery; and PPARalpha which is necessary for the fat-depletion of adipocytes for thermogenesis. The mRNA of lipogenic enzymes (acetyl-CoA carboxylase alpha, fatty-acid synthase and glycerol-3-phosphate acyltransferase), hormone sensitive lipase and beta1-adrenoceptor were also enhanced in white adipose tissue by the injection of 0.1 mg/kg per day risperidone. 6. These findings suggest that the materials for heat generation in white adipose tissue would be readily supplied, which in turn would reduce a storage of lipids in white adipose tissue resulting in the lower rate of bodyweight gain of rats.
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PMID:Resistance to excessive bodyweight gain in risperidone-injected rats. 1581 Sep 92

We have previously shown that several thyronamines, decarboxylated and deiodinated metabolites of the thyroid hormone, potently activate an orphan G protein-coupled receptor in vitro (TAAR1) and induced hypothermia in vivo on a rapid time scale [Scanlan, T. S.; Suchland, K. L.; Hart, M. E.; Chiellini, G.; Huang, Y.; Kruzich, P. J.; Frascarelli, S.; Crossley, D. A.; Bunzow, J. R.; Ronca-Testoni, S.; Lin, E. T.; Hatton, D.; Zucchi, R.; Grandy, D. K. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat. Med. 2004, 10 (6), 638-642]. Herein, we report the synthesis of these thyronamines. Additionally, a large number of thyroamine derivatives were synthesized in an effort to understand the molecular basis of TAAR1 activation and hypothermia induction. Several derivatives were found to potently activate both rTAAR1 and mTAAR1 in vitro (compounds 77, 85, 91, and 92). When administered to mice at a 50 mg/kg dose, these derivatives all induced significant hypothermia within 60 min and exhibited a hypothermic induction profile analogous to 3-iodothyronamine (1, T(1)AM) except 91, which proved to be more efficacious. On the basis of this result, a dose-dependent profile for 91 was generated and an ED(50) of 30 mumol/kg was calculated. Compound 91 proved to be more potent than T(1)AM for TAAR1 activation and exhibits increased potency and efficacy for hypothermia induction. These data further strengthen the pharmacological correlation linking TAAR1 activation by thyronamines and hypothermia induction in mice.
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PMID:Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues. 1645 Oct 74

Myxedema coma is the term given to the most severe presentation of profound hypothyroidism and is often fatal in spite of therapy. Decompensation of the hypothyroid patient into a coma may be precipitated by a number of drugs, systemic illnesses (eg, pneumonia), and other causes. It typically presents in older women in the winter months and is associated with signs of hypothyroidism, hypothermia, hyponatremia, hypercarbia, and hypoxemia. Treatment must be initiated promptly in an intensive care unit setting. Although thyroid hormone therapy is critical to survival, it remains uncertain whether it should be administered as thyroxine, triiodothyronine, or both. Adjunctive measures, such as ventilation, warming, fluids, antibiotics, pressors, and corticosteroids, may be essential for survival.
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PMID:Myxedema coma. 1712 41

The trace amine-associated receptor 1 (TAAR(1)) is a biogenic amine G protein-coupled receptor (GPCR) that is potently activated by 3-iodothyronamine (1, T(1)AM) in vitro. Compound 1 is an endogenous derivative of the thyroid hormone thyroxine which rapidly induces hypothermia, anergia, and bradycardia when administered to mice. To explore the role of TAAR(1) in mediating the effects of 1, we rationally designed and synthesized rat TAAR(1) superagonists and lead antagonists using the rotamer toggle switch model of aminergic GPCR activation. The functional activity of a ligand is proposed to be correlated to its probable interactions with the rotamer switch residues; agonists allow the rotamer switch residues to toggle to their active conformation, whereas antagonists interfere with this conformational transition. These agonist and antagonist design principles provide a conceptual model for understanding the relationship between the molecular structure of a drug and its pharmacological properties.
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PMID:Toward deciphering the code to aminergic G protein-coupled receptor drug design. 1842 Jan 41

Thyronamines are naturally occurring, chemical relatives of thyroid hormone. Systemic administration of synthetic 3-iodothyronamine (T(1)AM) and - to a lesser extent - thyronamine (T(0)AM), leads to acute bradycardia, hypothermia, decreased metabolic rate, and hyperglycemia. This profile led us to hypothesize that the central nervous system is among the principal targets of thyronamines. We investigated whether a low dose i.c.v. infusion of synthetic thyronamines recapitulates the changes in glucose metabolism that occur following i.p. thyronamine administration. Plasma glucose, glucoregulatory hormones, and endogenous glucose production (EGP) using stable isotope dilution were monitored in rats before and 120 min after an i.p. (50 mg/kg) or i.c.v. (0.5 mg/kg) bolus infusion of T(1)AM, T(0)AM, or vehicle. To identify the peripheral effects of centrally administered thyronamines, drug-naive rats were also infused intravenously with low dose (0.5 mg/kg) thyronamines. Systemic T(1)AM rapidly increased EGP and plasma glucose, increased plasma glucagon, and corticosterone, but failed to change plasma insulin. Compared with i.p.-administered T(1)AM, a 100-fold lower dose administered centrally induced a more pronounced acute EGP increase and hyperglucagonemia while plasma insulin tended to decrease. Both systemic and central infusions of T(0)AM caused smaller increases in EGP, plasma glucose, and glucagon compared with T(1)AM. Neither T(1)AM nor T(0)AM influenced any of these parameters upon low dose i.v. administration. We conclude that central administration of low-dose thyronamines suffices to induce the acute alterations in glucoregulatory hormones and glucose metabolism following systemic thyronamine infusion. Our data indicate that thyronamines can act centrally to modulate glucose metabolism.
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PMID:Central effects of thyronamines on glucose metabolism in rats. 1927 99

3-Iodothyronamine (T1AM) is a metabolite of thyroid hormone. It is an agonist at trace amine-associated receptor 1 (TAAR1), a recently identified receptor involved in monoaminergic regulation and a potential novel therapeutic target. Here, T1AM was studied using rhesus monkey TAAR1 and/or human dopamine transporter (DAT) co-transfected cells, and wild-type (WT) and TAAR1 knock-out (KO) mice. The IC(50) of T1AM competition for binding of the DAT-specific radio-ligand [(3)H]CFT was highly similar in DAT cells, WT striatal synaptosomes and KO striatal synaptosomes (0.72-0.81 microM). T1AM inhibition of 10 nM [(3)H]dopamine uptake (IC(50): WT, 1.4 + or - 0.5 microM; KO, 1.2 + or - 0.4 microM) or 50 nM [(3)H]serotonin uptake (IC(50): WT, 4.5 + or - 0.6 microM; KO, 4.7 + or - 1.1 microM) in WT and KO synaptosomes was also highly similar. Unlike other TAAR1 agonists that are DAT substrates, TAAR1 signaling in response to T1AM was not enhanced in the presence of DAT as determined by CRE-luciferase assay. In vivo, T1AM induced robust hypothermia in WT and KO mice equivalently and dose dependently (maximum change degrees Celsius: 50 mg/kg at 60 min: WT -6.0 + or - 0.4, KO -5.6 + or - 1.0; and 25 mg/kg at 30 min: WT -2.7 + or - 0.4, KO -3.0 + or - 0.2). Other TAAR1 agonists including beta-phenylethylamine (beta-PEA), MDMA (3,4-methylenedioxymethamphetamine) and methamphetamine also induced significant, time-dependent thermoregulatory responses that were alike in WT and KO mice. Therefore, TAAR1 co-expression does not alter T1AM binding to DAT in vitro nor T1AM inhibition of [(3)H]monoamine uptake ex vivo, and TAAR1 agonist-induced thermoregulatory responses are TAAR1-independent. Accordingly, TAAR1-directed compounds will likely not affect thermoregulation nor are they likely to be cryogens.
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PMID:Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. 2015 5


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