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1.
Hormones (Athens) ; 22(2): 295-304, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36810755

RESUMO

PURPOSE: Adolescence is a critical period of increased vulnerability to nutritional modifications, and adolescents may respond differently from adults to dietary intake and nutraceuticals. Cinnamaldehyde, a major bioactive compound of cinnamon, improves energy metabolism, as has been shown in studies conducted primarily in adult animals. We hypothesized that cinnamaldehyde treatment may have a higher impact on the glycemic homeostasis of healthy adolescent rats than on healthy adult rats. METHODS: Male adolescent (30 days) or adult (90 days) Wistar rats received cinnamaldehyde (40 mg/kg) for 28 days by gavage. The oral glucose tolerance test (OGTT), liver glycogen content, serum insulin concentration, serum lipid profile, and hepatic insulin signaling marker expression were evaluated. RESULTS: Cinnamaldehyde-treated adolescent rats showed less weight gain (P = 0.041), improved OGTT (P = 0.004), increased expression of phosphorylated IRS-1 (P = 0.015), and a trend to increase phosphorylated IRS-1 (P = 0.063) in the liver of adolescent rats in the basal state. None of these parameters was modified after treatment with cinnamaldehyde in the adult group. Cumulative food intake, visceral adiposity, liver weight, serum insulin, serum lipid profile, hepatic glycogen content, and liver protein expression of IRß, phosphorylated IRß, AKT, phosphorylated AKT, and PTP-1B in the basal state were similar between both age groups. CONCLUSION: In a healthy metabolic condition, cinnamaldehyde supplementation affects glycemic metabolism in adolescent rats while promoting no changes in adult rats.


Assuntos
Resistência à Insulina , Insulina , Ratos , Masculino , Animais , Glucose/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Lipídeos , Suplementos Nutricionais
2.
Int J Endocrinol ; 2019: 8919435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30723500

RESUMO

BACKGROUND: Increased platelet response is seen in individuals with metabolic syndrome. Previous reports have shown that arginine supplementation and aerobic exercise training enhance vascular nitric oxide (NO) activity and inhibit platelet hyperaggregability; however, the effects of their association remain unknown. AIM: To investigate whether arginine supplementation and aerobic exercise association may exert beneficial effects, reducing platelet hyperaggregability in rats under high risk to develop metabolic syndrome. METHODS: Wistar rats were divided into two groups: control (C) and fructose (F - water with 10% of fructose). After two weeks, the F group was subdivided into four groups: F, the same as before; fructose + arginine (FA - 880 mg/kg/day of L-arginine by gavage); fructose + training (FT); and fructose + arginine + training (FTA). Treatment lasted for eight weeks. RESULTS: The fructose administration was able to increase the collagen-induced platelet aggregation (27.4 ± 2.7%) when compared to the C group (8.0 ± 3.4%). Although the arginine supplementation (32.2 ± 6.3%) or aerobic training (23.8 ± 6.5%) did not promote any change in platelet collagen-induced hyperaggregability, the association of arginine supplementation and aerobic exercise promoted an inhibition of the platelet hyperaggregability induced by fructose administration (13.9 ± 4.4%) (P < 0.05). These effects were not observed when ADP was employed as an agonist. In addition, arginine supplementation associated with aerobic exercise promoted a decrease in interleukin-6 (IL-6) and interleukin-8 (IL-8) serum levels when compared to the fructose group, demonstrating an anti-inflammatory effect. CONCLUSIONS: Our data indicate an important role of arginine supplementation associated with aerobic exercise, reducing platelet hyperaggregability and inflammatory biomarker levels in rats under high risk to develop metabolic syndrome.

3.
J Mol Endocrinol ; 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-30006341

RESUMO

The modern concept of thyroid disruptors includes man-made chemicals and bioactive compounds from food that interfere with any aspect of the hypothalamus-pituitary-thyroid axis, thyroid hormone biosynthesis and secretion, blood and transmembrane transport, metabolism and local action of thyroid hormones. This review highlights relevant disruptors that effect populations through their diet: directly from food itself (fish oil and polyunsaturated fatty acids, pepper, coffee, cinnamon and resveratrol/grapes), through vegetable cultivation (pesticides) and from containers for food storage and cooking (bisphenol A, phthalates and polybrominated diphenyl ethers). Due to the vital role of thyroid hormones during every stage of life, we review effects from the gestational period through to adulthood, including evidence from in vitro studies, rodent models, human trials and epidemiological studies.

4.
Br J Nutr ; 118(1): 1-10, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28799895

RESUMO

Endothelial function is a key mechanism in the development of CVD. Arginine and exercise are important non-pharmacological strategies for mitigating the impact of metabolic changes in the metabolic syndrome, but the effect of their combined administration is unknown. Thus, the aim of this study was to investigate the isolated and combined effects of aerobic training and arginine supplementation on metabolic variables and vascular reactivity in rats at high risk for developing the metabolic syndrome. Wistar rats were divided into two groups: control and fructose (F - water with 10 % fructose). After 2 weeks, the F group was divided into four groups: F, fructose+arginine (FA, 880 mg/kg per d of l-arginine), fructose+training (FT) and fructose+arginine+training (FTA); treatments lasted for 8 weeks, and no difference was observed in body mass gain. Arginine did not improve the body protein content, and both the FA and FT groups show a reversal of the increase in adipose tissue. Insulin increase was prevented by training and arginine, without additive effect, and the increase in serum TAG was prevented only by training. The F group showed impaired endothelium-dependent vasodilation and hyperreactivity to phenylephrine, but arginine and training were capable of preventing these effects, even separately. Higher nitric oxide level was observed in the FA and FT groups, and no potentiating effect was detected. Thus, only training was able to prevent the increase in TAG and improve the protein mass, and training and arginine exert similar effects on fat content, insulin and endothelial function, but these effects are not additive.


Assuntos
Arginina/farmacologia , Endotélio Vascular/fisiologia , Síndrome Metabólica/prevenção & controle , Condicionamento Físico Animal/fisiologia , Tecido Adiposo/metabolismo , Animais , Composição Corporal/efeitos dos fármacos , Suplementos Nutricionais , Endotélio Vascular/efeitos dos fármacos , Frutose , Insulina/sangue , Masculino , Síndrome Metabólica/metabolismo , Óxido Nítrico/sangue , Fenilefrina/farmacologia , Proteínas/metabolismo , Ratos Wistar , Triglicerídeos/sangue
5.
J Sci Food Agric ; 97(11): 3855-3863, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28182286

RESUMO

BACKGROUND: Cinnamon supplementation has been associated with an improvement in glucose disposal and a reduction in fat mass in type 2 diabetes. Maternal nutrition during lactation impacts the health of the offspring throughout life. We hypothesize that cinnamon intake by lactating rats affects maternal physiology, leading to hormonal and metabolic changes in their offspring. To investigate this hypothesis, dams received aqueous cinnamon extract (400 mg cinnamon kg-1 body mass day-1 ) or water orally, during lactation. RESULTS: Maternal cinnamon intake did not affect the body mass gain or food intake of dams or their offspring, although it decreased visceral white adipose tissue mass in dams and in their adult offspring of both sexes. Cinnamon-treated dams exhibited no differences in serum insulin, adiponectin, leptin or estradiol levels, although they presented higher serum progesterone. At weaning, cinnamon male pups exhibited lower insulinemia, whereas cinnamon female pups exhibited lower glycemia. Interestingly, in adulthood, only the female offspring exhibited an altered hormonal profile, with reduced serum leptin, adiponectin and insulin levels accompanied by lower glycemia. CONCLUSION: The present study demonstrates that maternal cinnamon intake during lactation promotes mild changes in dams and can trigger sex-specific metabolic programming in pups that lasts into adulthood. © 2017 Society of Chemical Industry.


Assuntos
Cinnamomum zeylanicum/metabolismo , Hormônios/sangue , Lactação/metabolismo , Adiponectina/sangue , Tecido Adiposo Branco/metabolismo , Animais , Aleitamento Materno , Cinnamomum zeylanicum/química , Suplementos Nutricionais/análise , Estradiol/sangue , Feminino , Humanos , Insulina/sangue , Leptina/sangue , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Progesterona/sangue , Ratos , Ratos Wistar , Fatores Sexuais
6.
J Appl Physiol (1985) ; 121(1): 289-98, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27255525

RESUMO

Cardiovascular disease is the major cause of death worldwide; therefore it is important to understand the natural history of the pathophysiologic process and develop strategies to halt its progression. Thus this study investigated the protective effect of aerobic training on pathophysiological mechanisms involved in subclinical cardiometabolic alterations in a model with constant exposure to a prejudicial agent. Male Wistar rats were divided into a control group (C), which received drinking water, fructose group (F), which was fed 10% fructose in drinking water for 10 wk, and control training (CT) and fructose training groups (FT), in which moderate aerobic training was added in the last 8 wk of the study. Insulin, triacylglycerol, and isoprostane were higher and superoxide dismutase (SOD) was lower in the F group. There was no difference in thoracic aorta histology, but a decreased vascularization was seen in the F group, avoided by training in left ventricle. Regarding vascular function, the F group exhibited increased vasoconstrictory reactivity to phenylephrine. The F group presented impaired vasodilation to acetylcholine. Regarding endothelial nitric oxide synthase (eNOS), the F group presented a lower expression, and phosphorylated eNOS was higher in the trained groups than in their respective control groups. This same pattern was observed for nitric oxide bioavailability, antioxidant protein expression in aorta, left ventricle, and muscle (catalase, SOD, and glutathione peroxidase), serum SOD activity, and muscle mass. These results suggest that exercise training enhanced the antioxidant pathway and, as a consequence, the eNOS pathway, preventing an impairment in vascular vasodilatory capacity.


Assuntos
Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Óxido Nítrico/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Antioxidantes/metabolismo , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Insulina/metabolismo , Isoprostanos/metabolismo , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Oxirredução , Fenilefrina/farmacologia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Triglicerídeos/metabolismo , Vasoconstrição/fisiologia , Vasodilatação/fisiologia
7.
J Sci Food Agric ; 96(8): 2889-95, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26374392

RESUMO

BACKGROUND: Cinnamon has several effects on energy metabolism. However, no data exist on the impact of cinnamon intake on thyroid hormone serum concentrations and action, since thyroid hormones (THs) play a major role in metabolism. RESULTS: Male rats were treated with cinnamon water extract (400 mg kg(-1) body weight, 25 days). Cinnamon supplementation resulted in a lower serum total T3 level accompanied by normal serum T4 and TSH levels. The cinnamon-treated rats did not exhibit significant differences in TSHß subunit, TRß or deiodinase type 2 mRNA expression in the pituitary. In the liver, cinnamon did not change the TRß protein expression or the deiodinase type 1 mRNA expression, suggesting that there were no changes in T3 signaling or metabolism in this organ. However, mitochondrial GPDH, a target gene for T3 in the liver, exhibited no changes in mRNA expression, although its activity level was reduced by cinnamon. In the cardiac ventricle, T3 action was markedly reduced by cinnamon, as demonstrated by the lower TRα mRNA and protein levels, reduced SERCA2a and RyR2 and increased phospholamban mRNA expression. CONCLUSION: This study has revealed that TH action is a novel target of cinnamon, demonstrating impairment of T3 signaling in the cardiac ventricles. © 2015 Society of Chemical Industry.


Assuntos
Cinnamomum zeylanicum , Regulação da Expressão Gênica/efeitos dos fármacos , Receptores dos Hormônios Tireóideos/metabolismo , Tri-Iodotironina/sangue , Animais , Suplementos Nutricionais , Glicerolfosfato Desidrogenase/genética , Glicerolfosfato Desidrogenase/metabolismo , Coração/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Mitocôndrias Hepáticas , Miocárdio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores dos Hormônios Tireóideos/genética , Tireotropina/sangue , Tireotropina/metabolismo , Tiroxina/sangue , Tiroxina/metabolismo
8.
Food Funct ; 6(10): 3257-65, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26237537

RESUMO

In models of metabolic disorders, cinnamon improves glucose and lipid metabolism. This study explores the effect of chronic supplementation with aqueous cinnamon extract (CE) on the lipid metabolism of rats. Male adult Wistar rats were separated into a control group (CTR) receiving water and a CE Group receiving aqueous cinnamon extract (400 mg of cinnamon per kg body mass per day) by gavage for 25 consecutive days. Cinnamon supplementation did not change the food intake or the serum lipid profile but promoted the following changes: lower body mass gain (P = 0.008), lower relative mass of white adipose tissue (WAT) compartments (P = 0.045) and higher protein content (percentage of the carcass) (P = 0.049). The CE group showed lower leptin mRNA expression in the WAT (P = 0.0017) and an important tendency for reduced serum leptin levels (P = 0.059). Cinnamon supplementation induced lower mRNA expression of SREBP1c (sterol regulatory element-binding protein 1c) in the WAT (P = 0.001) and liver (P = 0.013) and lower mRNA expression of SREBP2 (P = 0.002), HMGCoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase) (P = 0.0003), ACAT1 (acetyl-CoA acetyltransferase 1) (P = 0.032) and DGAT2 (diacylglycerol O-acyltransferase 2) (P = 0.03) in the liver. These changes could be associated with the reduced esterified cholesterol and triacylglycerol content detected in this tissue. Our results suggest that chronic ingestion of aqueous cinnamon extract attenuates lipogenic processes, regulating the expression of key enzymes and transcriptional factors and their target genes, which are directly involved in lipogenesis. These molecular changes possibly promote adaptations that would prevent an increase in circulating cholesterol and triacylglycerol levels and prevent lipid accumulation in tissues, such as liver and WAT. Therefore, we speculate that cinnamon may also be useful for preventing or retarding the development of lipid disorders.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Cinnamomum zeylanicum/química , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Extratos Vegetais/farmacologia , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Acetiltransferase/metabolismo , Tecido Adiposo/metabolismo , Animais , Índice de Massa Corporal , Peso Corporal , Colesterol/sangue , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Leptina/genética , Leptina/metabolismo , Fígado/metabolismo , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteínas de Ligação a Elemento Regulador de Esterol/genética , Proteínas de Ligação a Elemento Regulador de Esterol/metabolismo , Triglicerídeos/sangue
9.
Regul Pept ; 194-195: 30-5, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25454367

RESUMO

Neuromedin B, a peptide highly expressed at the pituitary, has been shown to act as autocrine/paracrine inhibitor of thyrotropin (TSH) release. Here we studied the thyroid axis of adult female mice lacking neuromedin B receptor (NBR-KO), compared to wild type (WT) littermates. They exhibited slight increase in serum TSH (18%), with normal pituitary expression of mRNA coding for α-glycoprotein subunit (Cga), but reduced TSH ß-subunit mRNA (Tshb, 41%), lower intra-pituitary TSH content (24%) and increased thyroid hormone transporter MCT-8 (Slc16a2, 44%) and thyroid hormone receptor ß mRNA expression (Thrb, 39%). NBR-KO mice exhibited normal thyroxine (T4) and reduced triiodothyronine (T3) (30%), with no alterations in the intra-thyroidal content of T4 and T3 or thyroid morphological changes. Hypothalamic thyrotropin-releasing hormone (TRH) mRNA (Trh) was increased (68%), concomitant with a reduction in type 2 deiodinase mRNA (Dio2, 30%) and no changes in MCT-8 and thyroid hormone receptor mRNA expression. NBR-KO mice exhibited a 56% higher increase in serum TSH in response to an acute single intraperitoneal injection of TRH concomitant with a non-significant increase in pituitary TRH receptor (Trhr) mRNA at basal state. The phenotype of female NBR-KO mice at the hypothalamus-pituitary axis revealed alterations in pituitary and hypothalamic gene expression, associated with reduced serum T3, and higher TSH response to TRH, with apparently normal thyroid morphology and hormonal production. Thus, results confirm that neuromedin B pathways are importantly involved in secretory pathways of TSH and revealed its participation in the in vivo regulation of gene expression of TSH ß-subunit and pituitary MCT8 and Thrb and hypothalamic TRH and type 2 deiodinase.


Assuntos
Hipotálamo/metabolismo , Hipófise/metabolismo , Receptores da Bombesina/genética , Glândula Tireoide/metabolismo , Animais , Feminino , Camundongos , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores da Bombesina/deficiência , Receptores da Bombesina/metabolismo , Tireotropina/sangue , Tireotropina/metabolismo , Hormônio Liberador de Tireotropina/metabolismo
10.
Mol Cell Biol ; 34(18): 3450-60, 2014 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-25002528

RESUMO

Insulin and insulin-like growth factor 1 (IGF-1) receptor signaling pathways differentially modulate cardiac growth under resting conditions and following exercise training. These effects are mediated by insulin receptor substrate 1 (IRS1) and IRS2, which also differentially regulate resting cardiac mass. To determine the role of IRS isoforms in mediating the hypertrophic and metabolic adaptations of the heart to exercise training, we subjected mice with cardiomyocyte-specific deletion of either IRS1 (CIRS1 knockout [CIRS1KO] mice) or IRS2 (CIRS2KO mice) to swim training. CIRS1KO hearts were reduced in size under basal conditions, whereas CIRS2KO hearts exhibited hypertrophy. Following exercise swim training in CIRS1KO and CIRS2KO hearts, the hypertrophic response was equivalently attenuated, phosphoinositol 3-kinase (PI3K) activation was blunted, and prohypertrophic signaling intermediates, such as Akt and glycogen synthase kinase 3ß (GSK3ß), were dephosphorylated potentially on the basis of reduced Janus kinase-mediated inhibition of protein phosphatase 2a (PP2A). Exercise training increased peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) protein content, mitochondrial capacity, fatty acid oxidation, and glycogen synthesis in wild-type (WT) controls but not in IRS1- and IRS2-deficient hearts. PGC-1α protein content remained unchanged in CIRS1KO but decreased in CIRS2KO hearts. These results indicate that although IRS isoforms play divergent roles in the developmental regulation of cardiac size, these isoforms exhibit nonredundant roles in mediating the hypertrophic and metabolic response of the heart to exercise.


Assuntos
Metabolismo Energético , Coração/fisiologia , Proteínas Substratos do Receptor de Insulina/fisiologia , Mitocôndrias/fisiologia , Transdução de Sinais , Animais , Regulação da Expressão Gênica , Glicogênio/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fosfatidilinositol 3-Quinases/metabolismo , Isoformas de Proteínas , Natação , Fatores de Transcrição/metabolismo
11.
J Nutr Biochem ; 21(10): 935-40, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19793640

RESUMO

n-3 polyunsaturated fatty acids (PUFAs) present in fish oil (FO) potently decrease serum lipids, which is also an effect of thyroid hormones. Both PUFAs and thyroid hormones affect hepatic lipid metabolism, and here we hypothesized that a long-term diet rich in n-3 PUFAs would enhance thyroid hormone action in the liver. Female rats received isocaloric and normolipid diets containing either soybean oil (SO) or FO during lactation. Male offspring received the same diet as their dams since weaning until sacrifice when they were 11 weeks old. FO group, as compared to SO group, exhibited lower body weight since 5 weeks of age until sacrifice, with no alterations in food ingestion, lower retroperitoneal white fat mass and elevated inguinal fat mass relative to body weight, with unchanged water and lipid but reduced protein percentage in their carcasses. FO diet resulted in lower serum triglycerides and cholesterol. Serum total triiodothyronine, total thyroxine and thyrotropin were similar between groups. However, liver thyroid hormone receptor (TR) ß1 protein expression was higher in the FO group and correlated negatively with serum lipids. Liver 5'-deiodinase activity, which converts thyroxine into triiodothyronine, was similar between groups. However, the activity of hepatic mitochondrial glycerophosphate dehydrogenase, the enzyme involved in thermogenesis and a well-characterized target stimulated by T3 via TRß1, was higher in the FO group, suggesting enhancement of thyroid hormone action. These findings suggest that the increase in thyroid hormone signaling pathways in the liver may be one of the mechanisms by which n-3 PUFAs exert part of their effects on lipid metabolism.


Assuntos
Gorduras Insaturadas na Dieta/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Óleos de Peixe/farmacologia , Fígado/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos/metabolismo , Animais , Feminino , Fígado/metabolismo , Masculino , Ratos , Triglicerídeos/sangue
12.
Regul Pept ; 146(1-3): 213-7, 2008 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-17931717

RESUMO

Neuromedin B (NB), a neuropeptide highly concentrated in pituitary, has been proposed to be an inhibitor of thyrotropin (TSH) secretion. Previous study showed that mice with disruption of neuromedin B receptor (NBR-KO) have higher TSH release in response to thyrotropin-releasing hormone (TRH), although TSH seems to have decreased bioactivity. Here we examined in NBR-KO mice the response of TSH to thyroid hormone (TH) deprivation, obtained by methimazole treatment, or excess, obtained by acute and chronic TH administration. In response to hypothyroidism NBR-KO mice exhibited a lower magnitude increase in serum TSH compared to wild-type (WT) mice (1.7 vs. 3.3-times increase compared to euthyroid values, respectively, P<0.001). One hour after a single T4 injection (0.4 microg/100 g BW), WT and NBR-KO hypothyroid mice presented similar degree of serum TSH reduction (54%, P<0.05). However, 3 h after T4 administration, WT mice presented serum TSH similar to hypothyroid baseline, while NBR-KO mice still had decreased serum TSH (30% reduced in comparison to hypothyroid baseline P<0.05). T3 treatment of euthyroid mice for 21 days, with progressively increasing doses, significantly reduced serum TSH similarly in WT and NBR-KO mice. Also, serum T4 exhibited the same degree of suppression in WT and NBR-KO. In conclusion, disruption of neuromedin B receptor did not interfere with the sensitivity of thyroid hormone-mediated suppression of TSH release, but impaired the ability of thyrotroph to increase serum TSH in hypothyroidism, which highlights the importance of NB in modulating the set point of the hypothalamus-pituitary-thyroid axis at hypothyroidism.


Assuntos
Hipotireoidismo/sangue , Receptores da Bombesina/fisiologia , Tireotropina/sangue , Animais , Hipotireoidismo/induzido quimicamente , Masculino , Camundongos , Camundongos Knockout , Receptores da Bombesina/genética , Tireotropina/metabolismo
13.
J Clin Invest ; 115(9): 2517-23, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16100573

RESUMO

Thyroid hormone (TH) action is mediated by TH receptors (TRs), which are members of the nuclear hormone receptor superfamily. In vitro studies have demonstrated that TR activity is regulated by interactions with corepressor and coactivator proteins (CoRs and CoAs, respectively). TH stimulation is thought to involve dissociation of CoRs and recruitment of CoAs to the liganded TR. In contrast, negative regulation by TH is thought to occur via recruitment of CoRs to the liganded TR. The physiological role of CoAs bound to TRs, however, has yet to be defined. In this study, we used gene-targeting techniques to mutate the TR-beta locus within its activation function-2 (AF-2) domain (E457A). This mutation was chosen because it completely abolished CoA recruitment in vitro, while preserving normal triiodothyronine (T3) binding and CoR interactions. As expected, TH-stimulated gene expression was reduced in homozygous E457A mice. However, these animals also displayed abnormal regulation of the hypothalamic-pituitary-thyroid axis. Serum thyroxine, T3, and thyroid-stimulating hormone (TSH) levels and pituitary Tshb mRNA levels were inappropriately elevated compared with those of WT animals, and L-T3 treatment failed to suppress serum TSH and pituitary Tshb mRNA levels. Therefore, the AF-2 domain of TR-beta is required for positive and, paradoxically, for negative regulation by TH in vivo.


Assuntos
Conformação Proteica , Receptores beta dos Hormônios Tireóideos/química , Receptores beta dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Marcação de Genes , Glutationa Transferase/metabolismo , Histona Acetiltransferases , Humanos , Sistema Hipotálamo-Hipofisário/fisiologia , Iodeto Peroxidase/metabolismo , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Correpressor 1 de Receptor Nuclear , Coativador 1 de Receptor Nuclear , Mutação Puntual , Ligação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Glândula Tireoide/citologia , Glândula Tireoide/metabolismo , Receptores beta dos Hormônios Tireóideos/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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