Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
1.
J Biol Chem ; 295(7): 1926-1942, 2020 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-31914415

RESUMO

The current obesity pandemic results from a physiological imbalance in which energy intake chronically exceeds energy expenditure (EE), and prevention and treatment strategies remain generally ineffective. Approaches designed to increase EE have been informed by decades of experiments in rodent models designed to stimulate adaptive thermogenesis, a long-term increase in metabolism, primarily induced by chronic cold exposure. At the cellular level, thermogenesis is achieved through increased rates of futile cycling, which are observed in several systems, most notably the regulated uncoupling of oxidative phosphorylation from ATP generation by uncoupling protein 1, a tissue-specific protein present in mitochondria of brown adipose tissue (BAT). Physiological activation of BAT and other organ thermogenesis occurs through ß-adrenergic receptors (AR), and considerable effort over the past 5 decades has been directed toward developing AR agonists capable of safely achieving a net negative energy balance while avoiding unwanted cardiovascular side effects. Recent discoveries of other BAT futile cycles based on creatine and succinate have provided additional targets. Complicating the current and developing pharmacological-, cold-, and exercise-based methods to increase EE is the emerging evidence for strong physiological drives toward restoring lost weight over the long term. Future studies will need to address technical challenges such as how to accurately measure individual tissue thermogenesis in humans; how to safely activate BAT and other organ thermogenesis; and how to sustain a negative energy balance over many years of treatment.


Assuntos
Metabolismo Energético , Mitocôndrias/metabolismo , Obesidade/terapia , Termogênese , Tecido Adiposo Marrom/metabolismo , Peso Corporal , Gerenciamento Clínico , Ingestão de Energia/fisiologia , Humanos , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosforilação Oxidativa , Receptores Adrenérgicos beta/metabolismo
2.
Clin Endocrinol (Oxf) ; 72(5): 709-15, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20447070

RESUMO

CONTEXT: The substitution of liothyronine (L-T3) for levothyroxine (L-T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L-T3 for L-T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L-T3 and L-T4. DESIGN: Randomized, double-blind, cross-over intervention study. SETTING: NIH clinical center. PATIENTS: Ten thyroidectomized patients. INTERVENTIONS: Study participants were treated with L-T3 or L-T4 with a target TSH >or= 0.5

Assuntos
Terapia de Reposição Hormonal , Hipotireoidismo/tratamento farmacológico , Tiroxina/uso terapêutico , Tri-Iodotironina/uso terapêutico , Área Sob a Curva , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/cirurgia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Equivalência Terapêutica , Testes de Função Tireóidea , Tireoidectomia , Tireotropina/sangue , Tiroxina/farmacocinética , Resultado do Tratamento , Tri-Iodotironina/farmacocinética
3.
J Clin Invest ; 130(5): 2209-2219, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31961826

RESUMO

BACKGROUNDMirabegron is a ß3-adrenergic receptor (ß3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that ß3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of ß3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).


Assuntos
Acetanilidas , Tecido Adiposo Marrom , HDL-Colesterol/sangue , Resistência à Insulina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tiazóis , Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Tecido Adiposo Marrom/diagnóstico por imagem , Tecido Adiposo Marrom/metabolismo , Adolescente , Adulto , Apolipoproteína A-I/sangue , Biomarcadores/sangue , Feminino , Humanos , Tiazóis/administração & dosagem , Tiazóis/efeitos adversos , Bexiga Urinária Hiperativa/sangue , Bexiga Urinária Hiperativa/diagnóstico por imagem , Bexiga Urinária Hiperativa/tratamento farmacológico
4.
Thyroid ; 29(10): 1371-1379, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31364488

RESUMO

Background: L-triiodothyronine (LT3) is a substitute for levothyroxine (LT4) for thyroid cancer (TC) patients during the preparation for nuclear medicine procedures, and it is used in combination with LT4 in patients who do not respond to the standard treatment for hypothyroidism. This therapy is commonly done by using fixed doses, potentially resulting in supraphysiologic levels of triiodothyronine (T3). A good understanding of the LT3 pharmacokinetics (PK) is necessary to design combination treatment schemes that are able to maintain serum T3 levels within the reference range, but data on the PK of LT3 are conflicting. Here, we present a study designed to characterize the PK of LT3 in patients devoid of endogenous thyroid hormone production, and not receiving LT4 therapy. Methods: We performed an open-label, PK study in patients undergoing thyroid hormone withdrawal in preparation for nuclear medicine procedures for the evaluation and treatment of follicular-derived TC. LT3 was substituted for LT4 at a 1:3 mcg/mcg dosage ratio thrice daily for at least 30 days. PK of the last LT3 dose while at steady state and terminal elimination was assessed over 11 days. Thereafter, a PK study was performed following the nuclear medicine procedure in patients who volunteered for a second study. Results: Fourteen patients age 48.5 ± 16.0 years completed the last dose study and five completed the second PK study. PK analysis indicates a time to maximum serum concentration of 1.8 ± 0.32 hours and two distinct phases of linear elimination, with a fast distribution phase and slow elimination phases with half-lives of 2.3 ± 0.11 hours and 22.9 ± 7.7 hours, supporting a two-compartment model. PK modeling predicts that a twice-daily administration of low-dose LT3 (0.07 mcg/kg twice daily) in combination with LT4 can predictably increase the serum T3 concentration without significant peaks above the reference range. Conclusions: The PK of LT3 is well described by a two-compartment model that assumes elimination only from the sampling compartment, with a rapid distribution phase and a slow elimination phase. This information will contribute to design therapeutic strategies for LT3/LT4 combination therapies directed to maintain stable T3 serum levels.


Assuntos
Hipotireoidismo/tratamento farmacológico , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Tiroxina/uso terapêutico , Tri-Iodotironina/farmacocinética , Adulto , Desprescrições , Feminino , Terapia de Reposição Hormonal , Humanos , Hipotireoidismo/etiologia , Masculino , Pessoa de Meia-Idade , Cintilografia , Tireotropina/sangue , Tri-Iodotironina/uso terapêutico
5.
Diabetes ; 67(10): 2113-2125, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29980535

RESUMO

ß3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human ß3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in 12 healthy men given one-time randomized doses of placebo, the approved dose of 50 mg, and 200 mg of the ß3-AR agonist mirabegron. There was a more-than-dose-proportional increase in BAT metabolic activity as measured by [18F]-2-fluoro-D-2-deoxy-d-glucose positron emission tomography/computed tomography (medians 0.0 vs. 18.2 vs. 305.6 mL ⋅ mean standardized uptake value [SUVmean] ⋅ g/mL). Only the 200-mg dose elevated both nonesterified fatty acids (68%) and resting energy expenditure (5.8%). Previously undescribed increases in gallbladder size (35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human ß3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective ß3-AR agonists to treat obesity-related complications.


Assuntos
Acetanilidas/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Ácidos e Sais Biliares/metabolismo , Vesícula Biliar/efeitos dos fármacos , Vesícula Biliar/metabolismo , Receptores Adrenérgicos beta/metabolismo , Tiazóis/farmacologia , Tecido Adiposo Marrom/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Voluntários Saudáveis , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RNA Mensageiro/genética , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Termogênese/efeitos dos fármacos , Termogênese/genética , Adulto Jovem
6.
Thyroid ; 24(1): 19-26, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23902316

RESUMO

BACKGROUND: Thyroid hormones are important determinants of energy expenditure, and in rodents, adipose tissue affects thyroid hormone homeostasis via leptin signaling. The relationship between thyroid hormones and nutritional status in humans has been assessed primarily in drastic dietary or bariatric surgery interventions, while limited information is available on serial assessment of this axis during moderate, prolonged dietary restriction. METHODS: To evaluate the effects of moderate dietary restriction on thyroid hormone homeostasis, 47 subjects with a body mass index (BMI) of 25-45 kg/m(2) were enrolled in a longitudinal intervention study; 30 nonoverweight volunteers were also enrolled as controls. Overweight and obese subjects underwent a 12-month individualized dietary intervention aimed at achieving a 5-10% weight loss. RESULTS: The intervention resulted in a 6.3±0.9 kg (6.5±1.0%) weight loss. At baseline, thyrotropin (TSH) and T3 concentrations correlated significantly with fat mass (R=0.257, p=0.024 and R=0.318, p=0.005, respectively). After weight loss, T3 decreased significantly (from 112.7±3.1 to 101.8±2.6 ng/dL, p<0.001) in the absence of significant changes in TSH or free T4 (fT4). The decrease in serum T3 correlated with the decrease in weight (R=0.294, p<0.001). The T3:fT4 ratio decreased significantly (p=0.02) in individuals who lost >5% body weight. CONCLUSIONS: T3 concentration closely correlates with individual nutritional status, and moderate weight loss results in a decrease in T3 with minimal changes in other thyroid hormone homeostasis parameters. The data suggest that a decrease in peripheral conversion of the prohormone T4 into its hormonally active metabolite T3 is at least in part responsible for the observed changes in thyroid hormone homeostasis.


Assuntos
Homeostase , Hormônios Tireóideos/sangue , Tiroxina/sangue , Tri-Iodotironina/sangue , Redução de Peso , Tecido Adiposo/patologia , Adulto , Índice de Massa Corporal , Metabolismo Energético , Feminino , Humanos , Masculino , Obesidade/sangue , Glândula Tireoide/fisiologia , Tireotropina/sangue
7.
Cell Metab ; 19(2): 302-9, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24506871

RESUMO

Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.


Assuntos
Exercício Físico/fisiologia , Fatores de Crescimento de Fibroblastos/sangue , Fibronectinas/sangue , Adipócitos/metabolismo , Adipocinas/metabolismo , Tecido Adiposo Marrom/metabolismo , Adulto , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Fibronectinas/metabolismo , Humanos , Masculino , Estremecimento/fisiologia , Adulto Jovem
8.
J Clin Endocrinol Metab ; 98(5): E862-6, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23585666

RESUMO

CONTEXT: A recent trial showed that 1:3 µg:µg liothyronine (L-T3) substitution for levothyroxine (L-T4) achieving near-identical TSH levels resulted in a significant decrease in weight and cholesterol levels with no appreciable changes in cardiovascular parameters, suggesting a differential peripheral response to the therapy. OBJECTIVE: We characterized the pituitary-thyroid axis in hypothyroid patients receiving equivalent doses of L-T3 or L-T4 by escalating-dose TRH stimulation test. DESIGN: A secondary analysis of a L-T3 vs L-T4 therapy trial was performed. SETTING: The study was conducted at the National Institutes of Health. PATIENTS: Thirteen patients were studied. INTERVENTIONS: Escalating-dose (5, 15, and 200 µg) TRH stimulation test on both treatment arms. MAIN OUTCOME MEASURES: Study outcomes were peak serum TSH concentration (Cmax), time to peak TSH concentration (Tmax), area under the curve from 0 to 60 minutes (AUC0₋60) after TRH injection. RESULTS: Thirteen patients aged 51.2 ± 8.29 years completed escalating-dose TRH stimulation test. No significant difference between L-T3 and L-T4 treatments was observed in TSH Cmax or area under the curve. L-T4 resulted in a small but significantly shorter Tmax compared to L-T3 (3.5 ± 0.73 min on 200 µg TRH dose, P < .03). In addition, 5 µg TRH dose compared to 200 µg resulted in a shorter Tmax on both treatment arms (6.9 ± 0.59 min L-T3, 4 ± 0.3 min L-T4; P = .0002). CONCLUSIONS: The assessment of the dynamic pituitary response to escalating doses of TRH confirms that substitution of L-T3 for L-T4 on a 1:3 ratio achieves a near-identical degree of pituitary euthyroidism. Furthermore, the data suggest that lower doses of TRH might provide clinically relevant information of thyrotroph function, particularly when investigating partial pituitary insufficiency states.


Assuntos
Terapia de Reposição Hormonal , Hipotireoidismo/tratamento farmacológico , Hipófise/efeitos dos fármacos , Hormônio Liberador de Tireotropina , Tiroxina/uso terapêutico , Tri-Iodotironina/uso terapêutico , Adulto , Índice de Massa Corporal , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/fisiopatologia , Cinética , Masculino , Pessoa de Meia-Idade , Hipófise/metabolismo , Hipófise/fisiopatologia , Prolactina/sangue , Prolactina/metabolismo , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Tireotropina/metabolismo , Hormônio Liberador de Tireotropina/administração & dosagem
9.
J Clin Endocrinol Metab ; 98(7): E1218-23, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23780370

RESUMO

CONTEXT: The contribution of brown adipose tissue (BAT) to the energy balance in humans exposed to sustainable cold has not been completely established, partially because of measurement limitations of both BAT activity and energy expenditure (EE). OBJECTIVE: The objective of the study was to characterize the role of BAT activation in cold-induced thermogenesis (CIT). DESIGN: This study was a single-blind, randomized crossover intervention. SETTING: The study was conducted at the National Institutes of Health Clinical Center. STUDY PARTICIPANTS: Thirty-one healthy volunteers participated in the study. INTERVENTIONS: The intervention included mild cold exposure. MAIN OUTCOMES: CIT and BAT activation were the main outcomes in this study. METHODS: Overnight EE measurement by whole-room indirect calorimeter at 24 °C or 19 °C was followed by 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (PET) scan. After 36 hours, volunteers crossed over to the alternate study temperature under identical conditions. BAT activity was measured in a 3-dimensional region of interest in the upper torso by comparing the uptake at the two temperatures. RESULTS: Twenty-four volunteers (14 males, 10 females) had a complete data set. When compared with 24 °C, exposure at 19 °C resulted in increased EE (5.3 ± 5.9%, P < .001), indicating CIT response and mean BAT activity (10.5 ± 11.1%, P < .001). Multiple regression analysis indicated that a difference in BAT activity (P < .001), age (P = .01), and gender (P = .037) were independent contributors to individual variability of CIT. CONCLUSIONS: A small reduction in ambient temperature, within the range of climate-controlled buildings, is sufficient to increase human BAT activity, which correlates with individual CIT response. This study uncovers for the first time a spectrum of BAT activation among healthy adults during mild cold exposure not previously recognized by conventional PET and PET-computed tomography methods. The enhancement of cold-induced BAT stimulation may represent a novel environmental strategy in obesity treatment.


Assuntos
Tecido Adiposo Marrom/metabolismo , Metabolismo Energético , Termogênese , Tecido Adiposo Marrom/diagnóstico por imagem , Adiposidade , Adulto , Fatores Etários , Ar Condicionado , Calorimetria Indireta , Temperatura Baixa , Estudos Cross-Over , Feminino , Fluordesoxiglucose F18 , Humanos , Imageamento Tridimensional , Masculino , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Caracteres Sexuais , Método Simples-Cego , Adulto Jovem
10.
J Clin Endocrinol Metab ; 96(11): 3466-74, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21865366

RESUMO

CONTEXT: Levothyroxine (L-T(4)) therapy is based on the assumption that the conversion of T(4) into T(3) provides adequate amounts of active hormone at target tissues. However, in rodents, L-T(4) alone does not restore a euthyroid state in all tissues. Previous combination L-T(4)/liothyronine (L-T(3)) therapy trials focused on quality-of-life endpoints, and limited information is available on the effects on other measures of thyroid hormone action. OBJECTIVE: Our objective was to evaluate the efficacy of thyroid hormone replacement with L-T(4) or L-T(3) at doses producing equivalent normalization of TSH. PARTICIPANTS, DESIGN, AND SETTING: Fourteen hypothyroid patients participated in this randomized, double-blind, crossover intervention at the National Institutes of Health Clinical Center. INTERVENTIONS: L-T(3) or L-T(4) were administered thrice daily to achieve a target TSH from 0.5-1.5 mU/liter. Volunteers were studied as inpatients after 6 wk on a stable dose and at the target TSH. MAIN OUTCOME MEASURES: Serum thyroid hormones, lipid parameters, and indices of glucose metabolism were evaluated. RESULTS: No difference was observed in TSH between L-T(3) and L-T(4) treatments. L-T(3) resulted in significant weight loss [L-T(4), 70.6 ± 12.5, vs. L-T(3), 68.5 ± 11.9 kg (P = 0.009)] and in a 10.9 ± 10.0% decrease in total cholesterol (P = 0.002), 13.3 ± 12.1% decrease in low-density lipoprotein-cholesterol (P = 0.002), and an 18.3 ± 28.6% decrease in apolipoprotein B (P = 0.018). No significant differences were observed in high-density lipoprotein-cholesterol, heart rate, blood pressure, exercise tolerance, or insulin sensitivity. CONCLUSIONS: The substitution of L-T(3) for L-T(4) at equivalent doses (relative to the pituitary) reduced body weight and resulted in greater thyroid hormone action on the lipid metabolism, without detected differences in cardiovascular function or insulin sensitivity.


Assuntos
Hipotireoidismo/tratamento farmacológico , Tiroxina/uso terapêutico , Tri-Iodotironina/uso terapêutico , Adulto , Idoso , Apolipoproteínas B/sangue , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Colesterol/sangue , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Hipotireoidismo/sangue , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Hormônios Tireóideos/sangue , Tiroxina/administração & dosagem , Resultado do Tratamento , Tri-Iodotironina/administração & dosagem
11.
Thyroid ; 20(12): 1407-12, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21054208

RESUMO

BACKGROUND: The common Thr92Ala D2 polymorphism has been associated with changes in pituitary-thyroid axis homeostasis, but published results are conflicting. To investigate the effects of the Thr92Ala polymorphism on intrathyroidal thyroxine (T4) to triiodothyronine (T3) conversion, we designed prospective pharmacogenomic intervention aimed to detect differences in T3 levels after thyrotropin (TSH)-releasing hormone (TRH)-mediated TSH stimulation of the thyroid gland. METHODS: Eighty-three healthy volunteers were screened and genotyped for the Thr92Ala polymorphism. Fifteen volunteers of each genotype (Thr/Thr, Thr/Ala, and Ala/Ala) underwent a 500 mcg intravenous TRH stimulation test with serial measurements of serum total T3 (TT3), free T4, and TSH over 180 minutes. RESULTS: No differences in baseline thyroid hormone levels were seen among the study groups. Compared to the Thr/Thr group, the Ala/Ala group showed a significantly lower TRH-stimulated increase in serum TT3 at 60 minutes (12.07 ± 2.67 vs. 21.07 ± 2.86 ng/dL, p = 0.029). Thr/Ala subjects showed an intermediate response. Compared to Thr/Thr subjects, the Ala/Ala group showed a blunted rate of rise in serum TT3 as measured by mean time to 50% maximum delta serum TT3 (88.42 ± 6.84 vs. 69.56 ± 6.06 minutes, p = 0.028). Subjects attained similar maximal (180 minutes) TRH-stimulated TT3 levels. TRH-stimulated TSH and free T4 levels were not significantly different among the three genotype groups. CONCLUSIONS: The commonly occurring Thr92Ala D2 variant is associated with a decreased rate of acute TSH-stimulated T3 release from the thyroid consistent with a decrease in intrathyroidal deiodination. These data provide a proof of concept that the Thr92Ala polymorphism is associated with subtle changes in thyroid hormone homeostasis.


Assuntos
Iodeto Peroxidase/genética , Hormônio Liberador de Tireotropina , Tri-Iodotironina/metabolismo , Adulto , Estudos de Coortes , Humanos , Pessoa de Meia-Idade , Farmacogenética , Polimorfismo Genético , Estudos Prospectivos , Tiroxina/sangue , Tri-Iodotironina/sangue , Iodotironina Desiodinase Tipo II
12.
Eur J Endocrinol ; 163(6): 863-72, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20826525

RESUMO

OBJECTIVE: Resting energy expenditure (EE) is a major contributor to the total EE and thus plays an important role in body weight regulation. Adaptive thermogenesis is a major component of EE in rodents, but little is known on the effects of exposure of humans to mild and sustainable reduction in environmental temperature. DESIGN: To characterize the dynamic changes in continuously measured resting EE, substrate utilization, and hormonal axes simultaneously in response to mild reduction in environmental temperature, we performed a cross-over intervention. METHODS: Twenty-five volunteers underwent two 12-h recordings of EE in whole room indirect calorimeters at 24 and 19 °C with simultaneous measurement of spontaneous movements and hormonal axes. RESULTS: Exposure to 19 °C resulted in an increase in plasma and urine norepinephrine levels (P<0.0001), and a 5.96% (P<0.001) increase in EE without significant changes in spontaneous physical activity. Exposure to the lower temperature resulted in a significant increase in free fatty acid levels (P<0.01), fasting insulin levels (P<0.05), and a marginal decrease in postprandial glucose levels. A small but significant (P<0.002) increase in serum free thyroxine and urinary free cortisol (P<0.05) was observed at 19 °C. CONCLUSIONS: Our observations indicate that exposure to 19 °C, a mild and tolerable cold temperature, results in a predictable increase in EE driven by a sustained rise in catecholamine and the activation of counter-regulatory mechanisms.


Assuntos
Temperatura Baixa , Metabolismo Energético/fisiologia , Termogênese/fisiologia , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Meio Ambiente , Ácidos Graxos não Esterificados/sangue , Feminino , Homeostase/fisiologia , Humanos , Hidrocortisona/sangue , Insulina/sangue , Masculino , Pessoa de Meia-Idade , Atividade Motora , Norepinefrina/urina , Tiroxina/sangue
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA